@article {pmid42802831,
year = {2026},
author = {Miklitz, C and Shrestha, M and Philipp, W and Henk, N and Sprinkart, AM and Block, W and Luetkens, JA and Radbruch, A and Lehnen, NC and Nowak, S},
title = {Locally deployed large language model for real-world lecanemab eligibility pre-screening.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70495},
pmid = {42802831},
issn = {2352-8729},
abstract = {INTRODUCTION: The introduction of disease-modifying Alzheimer's therapies requires complex, labor-intensive patient screening. Cloud-based large language models (LLMs) could support this task but are often unsuitable for routine care due to data protection constraints.

METHODS: We evaluated an on-premises, open-weights LLM (gpt-oss-120b) for automated extraction of therapy-relevant variables for lecanemab eligibility from German memory clinic reports. In a two-stage design, LLM-based extraction prompts, a deterministic rule-based extractor, and a shared downstream rule-based classifier were optimized on a development set (n = 97) and evaluated on an independent hold-out set (n = 99), with expert consensus as ground truth.

RESULTS: The LLM-based pipeline achieved 94% accuracy and a Cohen's kappa of 0.90 on the hold-out set, significantly surpassing the rule-based comparator (80% accuracy) and demonstrating performance comparable to human experts.

DISCUSSION: A locally deployed, on-premises LLM may assist eligibility screening as a triage support tool, potentially facilitating access to novel therapies without compromising patient data privacy.},
}

@article {pmid42803225,
year = {2026},
author = {Jamhour, RMAQ and Salman, HA and Alshammari, M and Almuqati, AF and Fayed, MH and Al-Mazaideh, GM},
title = {Alzheimer's Disease: Silent Erosion of Memory - From Discovery to Modern Crisis and the Quest for a Cure.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050423446251215051844},
pmid = {42803225},
issn = {1875-5828},
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by a decline in cognitive abilities and memory impairment, representing the most common form of dementia worldwide. First described by Alois Alzheimer in 1906, AD continues to pose significant global health and socioeconomic challenges, with incidence anticipated to exceed 14 million cases by 2060. Despite decades of investigation, the specific pathophysiology -comprising multifactorial mechanisms such as genetic predisposition, environmental influences, lifestyle factors, amyloid-β (Aβ) plaques, neurofibrillary tangles, tau pathology, as well as vascular disease - remains incompletely understood. This review provides a comprehensive summary of the current knowledge regarding these mechanisms, and it explores the field's new therapeutic modalities, such as monoclonal antibodies, ultrasound-based treatments, and novel diagnostic tools based on biomarkers. It also discusses the socioeconomic burden of AD and regional challenges in the Middle East, as well as the impact of the COVID-19 pandemic on dementia care. While many of AD's underlying causes are aggressive and difficult to treat, new research in genetics, natural compounds, and groundbreaking therapies offers hope for better diagnosis and treatment. Above all, this study emphasizes the importance of having more effective chemotherapeutic or radiological approaches for ADs, as well as a robust medical system capable of providing these treatments to the patients.},
}

@article {pmid42803713,
year = {2026},
author = {Ippati, S and Torelli, F and Zamboni, G and Iavarone, A and Martorana, A and Botello, B and Cotton, S and Walker, C and Phillips, Z and Avitabile, A},
title = {Diagnosis and management of mild cognitive impairment and mild Alzheimer's disease dementia: Findings from an Italian real-world survey.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490595},
doi = {10.1177/13872877261490595},
pmid = {42803713},
issn = {1875-8908},
abstract = {BackgroundThe identification and early diagnosis of mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia are critical for timely intervention, yet implementation of biomarker-based diagnostics in the Italian healthcare system remains limited.ObjectiveTo characterize the real-world diagnostic journey, barriers, and management pathways of MCI and mild AD dementia patients in Italy.MethodsData were drawn from the Adelphi Real World Dementia Disease Specific Programme™, a cross-sectional survey of Italian primary care physicians and specialists. Physicians reported on diagnostic assessments, biomarker testing, and treatment initiation for consulting patients with MCI/mild AD dementia.ResultsPhysicians provided data on 325 patients (mean age: 74.1 years; 48.3% female). Patients aged ≥75 had lower Mini-Mental State Examination scores at survey (p = 0.0028) and diagnosis (p = 0.0223) than patients aged <75 years. Short-term memory loss (87.6%) was the most common symptom. Delays in diagnosis were most commonly attributed to limited specialist access (55.8%), prolonged interval between consultations (27.0%), and restricted diagnostic resources (20.4%). Magnetic resonance imaging was the primary imaging modality (65.7%), while biomarker testing such as cerebrospinal fluid and amyloid positron emission tomography were performed in 15.9% and 16.3% of cases, likely hindered by patient's reluctance and cost, respectively, as indicated by specialist-perceived challenges in using biomarkers for early symptomatic AD diagnosis. Patients whose treatment was initiated by specialists were commonly prescribed acetylcholinesterase inhibitors (72.8%).ConclusionsDelays in MCI and mild AD dementia diagnosis persist alongside systemic barriers and limited biomarker use. Improving referral pathways and biomarker access is essential for timely diagnosis and management.},
}

@article {pmid42803723,
year = {2026},
author = {Yeo, D and Kim, S and Lee, K and Son, Y and Lee, H and Kim, S and Hwang, HS and Yon, DK},
title = {Spirometry-defined obstructive airflow limitation and risk of incident dementia: A nationwide cohort study in South Korea.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261489594},
doi = {10.1177/13872877261489594},
pmid = {42803723},
issn = {1875-8908},
abstract = {BackgroundWhether spirometry-defined airflow limitation is independently associated with incident dementia and related disability burden remains unclear.ObjectiveTo investigate the association between obstructive airflow limitation and incident dementia and to estimate dementia-related years lived with disability (YLDs) in a nationwide cohort.MethodsWe conducted a nationwide population-based cohort study linking the Korea National Health and Nutrition Examination Survey (2014-2021) with national health insurance claims data. Adults aged ≥40 years with baseline spirometry and no prior dementia were included. Airflow limitation was defined as FEV1/FVC <0.70, with severity classified by percent-predicted FEV1. Inverse probability of treatment weighting balanced baseline covariates. Cox models estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for incident dementia. Dementia-related YLDs were calculated using Global Burden of Disease Study weights.ResultsDuring follow-up (2014-2023), 760 cases (4.79%) of dementia occurred among 15,854 adults. Normal pulmonary function was associated with lower dementia risk than airflow limitation (aHR, 0.62 [95% CI, 0.50-0.77]). Within the normal range, risk decreased across increasing FEV1/FVC tertiles (T1 [lowest], 0.76 [0.60-0.96]; T2, 0.63 [0.49-0.81]; T3 [highest], 0.45 [0.34-0.59]). Among those with airflow limitation, risk increased with severity (mild: 1.32 [0.95-1.84]; moderate: 1.87 [1.41-2.46]). Greater severity was also associated with higher YLDs.ConclusionsSpirometry-defined airflow limitation was associated with higher dementia risk and greater disability burden, suggesting impaired pulmonary function as a potential factor in dementia risk stratification and brain health.},
}

@article {pmid42803724,
year = {2026},
author = {Bruun, M and Rune Nielsen, T and Waldemar, G and Frederiksen, KS},
title = {Older adults' attitudes toward knowing their risk of Alzheimer's disease and preclinical diagnostic communication: A nationwide study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261489585},
doi = {10.1177/13872877261489585},
pmid = {42803724},
issn = {1875-8908},
abstract = {BackgroundCommunication about biomarkers and disclosure of Alzheimer's disease pathology is challenging. Earlier diagnosis has intensified this challenge, but evidence regarding communication of positive biomarker results for Alzheimer's disease to individuals with subjective cognitive decline remains limited.ObjectiveThe study aimed to investigate older adults' attitude toward knowing their risk of Alzheimer's disease, preferences regarding pre-biomarker counseling and diagnostic disclosure, and their views on the use of artificial intelligence in the diagnostic process when presented with a hypothetical scenario of subjective cognitive decline.MethodsWe conducted a cross-sectional nationwide questionnaire survey among an age-selected, sex- and residence-balanced sample from the Danish Civil Registration System where individuals with dementia, nursing home residency, or dementia medication use were excluded. An online questionnaire was sent to 30,000 participants.ResultsA total of 12,939 participants (aged 55-84 years, 53.3% female) answered at least one questionnaire item (response rate: 43.1%). More than two-thirds of the participants were interested in knowing their Alzheimer's disease risk status (76.4%). Information on treatment options, test reliability and risk prediction, along with written material, personal interaction and follow-up consultation, were rated as the most important topics. Simple graphical figures were preferred to accompany risk communication. Finally, 56.4% were positive toward use of artificial intelligence in diagnostics by physicians.ConclusionsOlder adults are interested in knowing their risk of developing Alzheimer's disease and trust physicians' use of artificial intelligence in the diagnostic process. Moreover, their preferences regarding information and methodology may help improve the current guidelines.},
}

@article {pmid42803728,
year = {2026},
author = {Ali, M and Shabbir, H and Shaharyar, M and Mukesh, S and Rodriguez, A and Afshani, M and Kalra, D and Koriesh, A},
title = {Efficacy and safety of aducanumab, lecanemab, and donanemab in Alzheimer's disease: A meta-analysis of randomized controlled trials.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488812},
doi = {10.1177/13872877261488812},
pmid = {42803728},
issn = {1875-8908},
abstract = {BackgroundAnti-amyloid monoclonal antibodies offer a treatment strategy for early Alzheimer's disease, but their modest efficacy must be weighed against important safety concerns.ObjectiveTo evaluate the efficacy and safety of aducanumab, lecanemab, and donanemab in randomized placebo-controlled trials.MethodsPubMed, Cochrane, and ClinicalTrials.gov were searched through February 2026 for randomized placebo-controlled trials evaluating aducanumab, lecanemab, or donanemab in early symptomatic Alzheimer's disease. Outcomes included Clinical Dementia Rating-Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Mini-Mental State Examination (MMSE), amyloid-related imaging abnormalities-edema/effusion (ARIA-E), amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H), and APOE ε4-stratified ARIA-E. Random-effects meta-analyses were performed.ResultsSeven trials were included. Treatment favored intervention for ADAS-Cog (SMD -0.15, 95% CI -0.21 to -0.10), CDR-SB (MD -0.41, 95% CI -0.63 to -0.18), and MMSE (MD 0.44, 95% CI 0.03 to 0.86), although effects were small. Treatment increased ARIA-E (23.9% versus 1.9%; RR 11.65, 95% CI 9.06 to 14.99) and ARIA-H (16.8% versus 6.8%; RR 2.45, 95% CI 1.94 to 3.09). Among treated participants with APOE ε4-stratified ARIA-E data, APOE ε4 carriers had higher ARIA-E risk than non-carriers (29.3% versus 13.8%; RR 2.10, 95% CI 1.67 to 2.64). Brain-volume loss, ventricular enlargement, and treatment-related deaths were narratively identified but not pooled.ConclusionsAducanumab, lecanemab, and donanemab showed statistically significant but small slowing of decline that may not reach patient-perceptible clinical meaningfulness. Increased ARIA risk and additional safety signals support cautious selection, imaging surveillance, and individualized risk-benefit discussions.},
}

@article {pmid42803964,
year = {2026},
author = {Joshi, N and Vaidya, B and Saha, P and Kashyap, M and Sharma, SS},
title = {Clemizole, a TRPC5 channel blocker rescues amyloid-β toxicity and cognitive impairment by modulating mitochondrial dysfunction and memory-related proteins.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42803964},
issn = {1432-1912},
abstract = {Amyloid β (Aβ)-induced neuronal dysfunction is a key pathological feature of Alzheimer's disease (AD), characterized by oxidative stress, mitochondrial impairment, and calcium dyshomeostasis. Transient receptor potential canonical 5 (TRPC5), a calcium-permeable cation channel, has been implicated in neurodegeneration, but its role in AD remains unclear. This study investigated TRPC5 involvement in Aβ-induced neurotoxicity and evaluated the neuroprotective potential of Clemizole, a TRPC5 blocker, in preclinical AD models. In SH-SY5Y cells, Aβ-induced neurotoxicity was assessed by measuring cell viability, intracellular and mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, and calcium influx. In rats, an intracerebroventricular (ICV) Aβ25-35 (10 μg) induced cognitive impairment model was used. Behavioral tests assessed cognitive function. Hippocampal TRPC5 expression and memory as well as calcium associated protein expressions (p-CaMKII, PSD-95, BDNF, calcineurin A) were analyzed, and acetylcholinesterase (AChE) activity was measured following 3 weeks of Clemizole (10 and 30 mg/kg) treatment. Aβ exposure reduced neuronal survival, increased ROS, disrupted mitochondrial membrane potential, and elevated calcium influx in vitro. Clemizole mitigated oxidative stress, restored mitochondrial function, and restored calcium homeostasis. In vivo, Aβ induced cognitive deficits and upregulated hippocampal TRPC5 expression in rats. Clemizole reduced TRPC5 levels, improved cognitive performance, enhanced p-CaMKII, PSD-95, and BDNF expression, decreased calcineurin A, and reduced AChE activity. TRPC5 contributes to Aβ-induced neurotoxicity and cognitive impairment, and Clemizole-mediated TRPC5 inhibition confers neuroprotection by restoring calcium balance and attenuating the decrease in memory-associated protein expression. These findings support TRPC5 as a potential therapeutic target in AD; however, further studies using a transgenic AD model are warranted before clinical translation.},
}

@article {pmid42807347,
year = {2026},
author = {Albarrán Morillo, C and Zheng, L and Ghanbarian, E and Khorsand, B and Glover, CM and Grill, JD and Sajjadi, SA and Ezzati, A},
title = {APOE and amyloid-tau pathology in cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70496},
pmid = {42807347},
issn = {2352-8729},
abstract = {INTRODUCTION: Apolipoprotein E (APOE) genotype shows well-established dose-dependent associations with higher amyloid in cognitively unimpaired (CU) adults. In contrast, associations with tau burden and cognition are less well characterized.

METHODS: We performed a cross-sectional analysis of CU participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4), Alzheimer's Disease Neuroimaging Initiative (ADNI), Wisconsin Registry for Alzheimer's Prevention (WRAP), and National Alzheimer's Coordinating Center (NACC) within the harmonized multi-cohort Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC) data. A total of 4380 CU participants were included with APOE genotype, amyloid PET, and cognitive data (memory, language, executive, and visuospatial function), including a subset of 758 with tau PET imaging.

RESULTS: Compared with ε33, ε24 (β = 18.340), ε34 (β = 23.850), and ε44 (β = 44.820) showed higher amyloid burden (all p < .001). Similarly, ε24 (OR = 4.180), ε34 (OR = 4.540), and ε44 (OR = 14.150) had higher odds of amyloid positivity (all p < .001). After adjustment for amyloid burden, ε4 carriers had higher tau burden in the entorhinal cortex (β = 0.026; false discovery rate [FDR] -adjusted p = 0.041) and amygdala (β = 0.040; FDR-adjusted p = 0.003). Higher tau burden was associated with lower memory (β = -0.439; FDR-adjusted p = 0.012) and language performance (β = -0.610; FDR-adjusted p = 0.020).

DISCUSSION: APOE ε4 showed a strong dose-dependent association with amyloid, with the highest levels observed among ε4 homozygotes. Associations between APOE and global tau were more modest and appeared to be driven mainly by ε4 homozygotes, while regional analyses showed localized APOE ε4-related associations in medial temporal regions. Independently, higher tau was associated with lower memory and language performance.},
}

@article {pmid42807723,
year = {2026},
author = {Quan, Q and Pan, R and Liu, H and Zheng, L and Zhang, R},
title = {Potential Role of Red Yeast Rice in the Prevention and Treatment of Alzheimer's Disease.},
journal = {International journal of medical sciences},
volume = {23},
number = {10},
pages = {3101-3111},
pmid = {42807723},
issn = {1449-1907},
mesh = {*Alzheimer Disease/prevention & control/drug therapy/diet therapy ; Humans ; *Biological Products/therapeutic use/pharmacology/chemistry ; Monascus/metabolism/chemistry ; Antioxidants/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; Lovastatin/therapeutic use/pharmacology ; Amyloid beta-Peptides/metabolism ; gamma-Aminobutyric Acid/therapeutic use/pharmacology ; Fermentation ; },
abstract = {Red Yeast Rice (RYR) fermented from Monascus is a traditional fermented product with both dietary and medicinal uses and is widely used for lipid regulation. Clinically, it is utilized to lower blood lipid levels and manage hyperlipidemia. Contemporary research indicates that RYR is abundant in secondary metabolites, such as monacolin K, Monascus pigments, and γ-aminobutyric acid, which contribute to its lipid-lowering, blood sugar-reducing, anti-inflammatory, neuroprotective, and antihypertensive properties. These metabolites may play a significant role in the prevention and treatment of Alzheimer's disease (AD) through mechanisms that include cholesterol-dependent pathways, anti-neuroinflammation, antioxidant activity, neuroprotection, modulation of intestinal flora, inhibition of high-risk factors for AD, and suppression of AD-related β-amyloid peptide deposition and tau protein hyperphosphorylation. Consequently, RYR demonstrates potential for a multi-component synergistic approach to preventing and treating AD. However, current research on the use of RYR for AD prevention and treatment remains limited. This review focuses on the primary functional substances in RYR, elucidates the anti-AD effects and mechanisms of each metabolite, analyzes the advantages of its multi-component and multi-target properties, and provides a foundation for the further development of RYR.},
}

*Alzheimer Disease/prevention & control/drug therapy/diet therapy
Humans
*Biological Products/therapeutic use/pharmacology/chemistry
Monascus/metabolism/chemistry
Antioxidants/therapeutic use/pharmacology
Neuroprotective Agents/therapeutic use/pharmacology
Lovastatin/therapeutic use/pharmacology
Amyloid beta-Peptides/metabolism
gamma-Aminobutyric Acid/therapeutic use/pharmacology
Fermentation

@article {pmid42808238,
year = {2026},
author = {Kuzuya, A and Ohara, T and Akamatsu, N},
title = {Plain language summary of the mechanisms behind epilepsy in Alzheimer's disease and the use of perampanel.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/14737175.2026.2733194},
pmid = {42808238},
issn = {1744-8360},
}

@article {pmid42808496,
year = {2026},
author = {Park, BY and Jo, SW and Park, TY and Kim, H and Kim, MS and Kang, SY and Cho, SJ and Kim, J and Kim, S},
title = {Feasibility and safety of repeated low-intensity ultrasound in amyloid PET-positive early Alzheimer's disease: A prospective pilot study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493067},
doi = {10.1177/13872877261493067},
pmid = {42808496},
issn = {1875-8908},
abstract = {BackgroundLow-intensity ultrasound (LIUS) is a potential noninvasive neuromodulatory approach for Alzheimer's disease (AD), but clinical evidence on repeated stimulation in biomarker-confirmed early AD remains limited.ObjectiveTo evaluate the feasibility, safety, and exploratory clinical effects of a 4-week repeated LIUS protocol in amyloid positron emission tomography (PET)-positive early AD.MethodsTwenty patients with amyloid PET-positive prodromal AD or mild AD dementia underwent LIUS targeting bilateral frontal and temporal regions three times weekly for 4 weeks. Safety was assessed by neurological examinations and brain magnetic resonance imaging (MRI). Exploratory outcomes included the Trail Making Test-Black & White (TMT-B&W) parts A and B, Attention Questionnaire Scale (AQS), Korean version of Quality of Life (KQoL), Mini-Mental State Examination (MMSE), and Neuropsychiatric Inventory (NPI). Resting-state functional MRI was analyzed in an exploratory subset.ResultsNo severe adverse events occurred, and post-treatment MRI showed no intracerebral hemorrhage, microbleeding, or brain edema. Completion times decreased on TMT-B&W part A (105.3 ± 63.3 versus 84.2 ± 46.6 s, p = 0.012) and part B (280.1 ± 139.9 versus 212.8 ± 59.7 s, p = 0.038). NPI scores also decreased (9.8 ± 14.7 versus 4.5 ± 8.8, p = 0.006). KQoL, AQS, and MMSE did not change significantly.ConclusionsRepeated LIUS over 4 weeks was feasible and well tolerated in amyloid PET-positive early AD. Exploratory changes in executive function and neuropsychiatric symptoms were observed; however, the single-arm design precludes causal inference. Randomized, sham-controlled studies are warranted to determine the therapeutic potential of LIUS.},
}

@article {pmid42797438,
year = {2026},
author = {Gecili, İ and Ertuğrul, MS and Okkay, IF and Şenol, O and Okkay, U and Özkaraca, M and Al-Yaqoobi, Z and Bayram, C and Abd El-Aty, AM and Taghizadehghalehjoughi, A and Hacımüftüoğlu, A},
title = {Early Neuroprotective Effects of Erucic Acid and Gentisic Acid on Hippocampal Glutamate Concentrations and Alzheimer-like Molecular Alterations in an Intracerebroventricular Streptozotocin Rat Model.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
pmid = {42797438},
issn = {1424-8247},
support = {TDK-2021-9100//Atatürk University/ ; },
abstract = {Background: Alterations in glutamatergic homeostasis have been implicated in Alzheimer's disease, but the relationship between total hippocampal tissue glutamate and Alzheimer-like molecular alterations remains unclear. This study evaluated the early neuroprotective potential of gentisic acid (GA) and erucic acid (EA) in an intracerebroventricular streptozotocin (icv-STZ)-induced rat model of sporadic Alzheimer-like pathology. Methods: Sixty-four female Sprague-Dawley rats were randomly assigned to eight groups: control, sham, STZ, STZ + GA (100 or 200 mg/kg/day), STZ + EA (25 or 50 mg/kg/day), and STZ + memantine (10 mg/kg/day). Treatments began immediately after STZ and continued orally for 21 days. Behavioral performance was assessed by Morris water maze and passive avoidance tests. Total hippocampal tissue glutamate was quantified by LC-MS/MS. Neuronal degeneration was assessed histopathologically, whereas tau, amyloid-β, and AChE immunoreactivity and tau-, APP-, and AChE-related in situ hybridization signals were evaluated. Results: Compared with controls, STZ-treated rats exhibited poorer behavioral performance, higher total hippocampal tissue glutamate, greater neuronal degeneration, and increased molecular signals. GA and EA administration was associated with attenuation of these alterations, with generally stronger effects at higher doses. EA at 50 mg/kg/day showed the lowest mean total hippocampal tissue glutamate among treatment groups. GA at 200 mg/kg/day and EA at 50 mg/kg/day showed the most consistent preservation across behavioral, histopathological, and molecular endpoints. Conclusions: Early GA and EA administration was associated with neuroprotective effects in the icv-STZ model. Because treatment began immediately after STZ administration, the findings support early or preventive neuroprotection rather than reversal of established Alzheimer-like pathology. Total tissue glutamate measurements neither distinguish extracellular glutamate nor directly demonstrate glutamate-mediated excitotoxicity.},
}

@article {pmid42797479,
year = {2026},
author = {Bustelli, IB and Graça, SC and Santos, ÉVD and Lanaro, R and Linardi, A and Caetano, AL},
title = {Effects of Chronic Banisteriopsis caapi Extract Administration on Fibrillar Amyloid Deposition and Microglial Morphology in Aged PDGFB-APPSwInd Mice.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
pmid = {42797479},
issn = {1424-8247},
support = {2021/02469-2//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2021/06490-6//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 004/2022//Faculdade de Ciências Médicas da Santa Casa de São Paulo/ ; },
abstract = {Background/Objectives:Banisteriopsis caapi contains β-carboline alkaloids with neuropharmacological and immunomodulatory properties, but their effects during prolonged exposure in established amyloid pathology remain poorly characterized. This study investigated whether chronic intermittent B. caapi administration modifies behavioral performance, fibrillar amyloid pathology, and hippocampal microglial alterations in aged PDGFB-APPSwInd mice. Methods: Male wild-type (WT) and PDGFB-APPSwInd transgenic (TG) mice aged 15-18 months received B. caapi extract (1.5 mL/kg, oral gavage) or vehicle twice weekly for four weeks. Locomotor activity, anxiety-like behavior, and spatial recognition memory were assessed using the open-field, elevated-plus-maze, and object-location tests, respectively. Hippocampal fibrillar amyloid plaques were evaluated by Thioflavin-S staining, and microglial immunoreactivity and morphology were assessed using Iba1 immunofluorescence and morphometric analysis. Results: Chronic B. caapi administration did not consistently modify locomotor activity, anxiety-like behavior, or spatial recognition memory. In TG mice, treatment increased the number of hippocampal Thioflavin-S-positive fibrillar amyloid plaques, without corresponding changes in total Thioflavin-S-positive area or median plaque size. Microglial alterations were predominantly genotype-associated, with TG mice exhibiting changes in Iba1-labeled cell quantification and morphology, particularly in the CA1 region. B. caapi treatment did not significantly modify these genotype-associated morphological alterations. Conclusions: Chronic intermittent B. caapi exposure was associated with a selective change in fibrillar amyloid plaque number without parallel changes in plaque area, plaque size, behavioral performance, or microglial morphology. These findings expand current evidence regarding the biological effects of repeated B. caapi exposure in the context of established amyloid pathology.},
}

@article {pmid42798750,
year = {2026},
author = {Shimohama, S and Bun, S and Shikimoto, R and Tomioka, H and Takayama, T and Mimura, Y and Sasaguri, H and Sekiguchi, K and Nishimoto, Y and Iwabuchi, Y and Tabuchi, H and Nakahara, J and Mimura, M and Ito, D},
title = {Real-world implementation of lecanemab in Alzheimer's disease: A Japanese cohort.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70492},
pmid = {42798750},
issn = {2352-8729},
abstract = {INTRODUCTION: Real-world evidence for lecanemab remains limited, particularly among Asian populations. We evaluated the feasibility, safety, biomarker profiles, and short-term clinical outcomes of lecanemab in practice in Japan.

METHODS: We screened 321 patients with early Alzheimer's disease (AD) and confirmed amyloid pathology using amyloid positron emission tomography (PET) or cerebrospinal fluid analysis. Plasma amyloid-β42/40 was assessed when available. Among these, 102 initiated lecanemab and underwent structured magnetic resonance imaging (MRI) surveillance with 6 months of follow-up.

RESULTS: Most treated patients had a Clinical Dementia Rating-Global (CDR-Global) score of 0.5 (96.1%), and 6-month treatment persistence exceeded 85%. Amyloid-related imaging abnormalities (ARIA), predominantly mild and asymptomatic ARIA-H, occurred in 11.4%, whereas no cases of isolated ARIA with effusion or edema (ARIA-E) were observed. One macrohemorrhagic and two moderate-severe radiographic ARIA with hemorrhage or hemosiderin deposition (ARIA-H) developed, which led to discontinuation of the treatment. Cognitive and functional measures remained generally stable over 6 months, with changes comparable to those reported in the phase 3 CLARITY-AD trial. Plasma-PET discordance highlighted the complementary value of multimodal biomarker interpretation.

DISCUSSION: Lecanemab was feasible and generally well tolerated under structured MRI monitoring in routine Japanese practice.},
}

@article {pmid42799832,
year = {2026},
author = {Hasan, A and Asfour, AAR and Qaba, H and Al-Sharabi, AA and Asfoor, A and Mohammed, S and Al-Adhreai, A and Güner, S and ALSaeedy, M},
title = {Mast Cells in Neuroimmune Interactions: Mechanisms, Pathophysiological Roles, and Therapeutic Implications.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42799832},
issn = {1559-1182},
mesh = {*Mast Cells/immunology/pathology/metabolism ; Humans ; Animals ; *Neuroimmunomodulation/physiology ; },
abstract = {Mast cells (MCs) are versatile immune cells that play a key role in neuroimmune interactions due to their strategic localization in barrier tissues and perineuronal sites, including the meninges, choroid plexus, thalamus, hypothalamus, and hippocampus within the central nervous system (CNS), as well as peripheral sites such as the skin, gastrointestinal tract, and dorsal root ganglia. They rapidly release stored and newly synthesized mediators, including histamine, tryptase, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), substance P, and prostaglandins, which regulate nerve signaling, vascular function, and inflammation. This review presents a framework integrating MC differentiation with distinct CNS microenvironments to explain their neuroprotective and toxic roles. The anatomical and molecular basis of MC-neuron interaction is discussed, with emphasis on bidirectional signaling via neuropeptides, neurotransmitters, and cytokines. MC functions in the CNS are highlighted, including neuroprotection through synaptic plasticity and BBB integrity under homeostatic conditions, as well as neurotoxicity, where aberrant activation promotes BBB breakdown, microglial priming, and neuroinflammatory cascades. Furthermore, the roles in which mast cell dysfunction is implicated in neurodegenerative and psychiatric disorders are examined, including Alzheimer's disease (AD), where amyloid-β triggers MC degranulation, Parkinson's disease (PD), where α-synuclein induces MC activation, multiple sclerosis (MS), autism, anxiety, and depression, as well as peripheral neuroimmune conditions affecting the skin, gut-brain axis, and pain. Current and emerging mast cell-targeted therapies, including stabilizers, histamine receptor blockers, tryptase inhibitors, and anti-IgE biologics, are discussed, along with future challenges in mast cell-based neuroimmunological treatment.},
}

*Mast Cells/immunology/pathology/metabolism
Humans
Animals
*Neuroimmunomodulation/physiology

@article {pmid42800042,
year = {2026},
author = {Ho, BL and Yang, YH},
title = {Blood-based biomarkers in the anti-amyloid era of Alzheimer's disease: clinical utility, implementation challenges, and future directions.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17582024.2026.2734618},
pmid = {42800042},
issn = {1758-2032},
abstract = {BACKGROUND: Implementation of disease-modifying anti-amyloid therapies for Alzheimer's disease remains constrained by the cost and procedural burden of positron emission tomography and cerebrospinal fluid testing. This review evaluates blood-based biomarkers in therapeutic pathways.

METHODS: PubMed/MEDLINE and Embase were searched for literature published from January 2018 onward, with earlier landmark studies included when relevant. Evidence was synthesized on plasma biomarkers in treatment eligibility, biological staging, longitudinal monitoring, therapeutic response, and risk stratification for amyloid-related imaging abnormalities.

RESULTS: Among assays, plasma p-tau217 consistently demonstrates the highest diagnostic accuracy for detecting cortical amyloid pathology across clinical settings. The plasma p-tau217/Aβ1-42 ratio is the first blood-based assay cleared by the FDA to identify amyloid pathology, supporting clinical triage. Complementary biomarkers, including plasma Aβ42/40, glial fibrillary acidic protein, and neurofilament light chain, reflect amyloid burden, astroglial activation, and neurodegeneration. Clinical adoption remains limited by inter-assay variability, inconsistent diagnostic thresholds, and the lack of surrogate endpoints for treatment monitoring and adverse-event assessment.

CONCLUSIONS: Blood-based biomarkers are best incorporated into structured, stepwise diagnostic and therapeutic frameworks rather than replacing established reference standards. Progress will require assay harmonization, prospective validation, and interpretable biomarker-guided care pathways to support scalable, safe implementation of disease-modifying therapies in routine dementia care.},
}

@article {pmid42800673,
year = {2026},
author = {de Leve, SJ and Wang, X and Alavifard, H and Dara, L and DeLeve, LD},
title = {Reversing liver sinusoidal endothelial aging restores clearance of amyloid-beta and LDL.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113608},
doi = {10.1016/j.jbc.2026.113608},
pmid = {42800673},
issn = {1083-351X},
abstract = {In healthy liver, large macromolecules pass freely into the space of Disse through liver sinusoidal endothelial cell (LSEC) fenestration. In aging, LSEC fenestration is largely lost (pseudocapillarization). We hypothesized that restoring aged LSECs' fenestration would enhance passage into the space of Disse of large-diameter (>50 nm) triglyceride-rich lipoproteins to which the majority of circulating amyloid-beta is bound and permit hepatocyte uptake of amyloid-beta: in aged rats, two weeks of the soluble guanylate cyclase activator cinaciguat restored fenestration; circulating amyloid-beta 40 levels halved, returning to levels found in young rats. Surprisingly, cinaciguat also reversed age-related increases in LDL (a smaller, 20-30 nm diameter lipoprotein), which crosses the sinusoidal endothelial barrier even when LSECs are defenestrated. We therefore investigated additional mechanisms by which LSECs promote hepatocyte clearance. Whereas primary hepatocytes had minimal uptake of amyloid-beta 40 or LDL, hepatocytes cultured in young rat LSEC conditioned medium retained their uptake function. Aged rat LSEC conditioned medium did not facilitate hepatocyte amyloid-beta 40 and LDL uptake but treating aged rats with cinaciguat restored aged rat LSECs paracrine signaling. We discovered that heparin-binding epidermal growth factor-like growth factor (HB-EGF) mediates this LSEC-hepatocyte interaction and that HB-EGF is synthesized but not secreted by aged rat LSECs; cinaciguat treatment restores aged LSECs' HB-EGF secretion. Treatment reversed age-associated loss of LDLR and LRP1 surface expression in rat hepatocytes. This study identifies a candidate therapy to address age-related increases in circulating amyloid-beta and LDL and elucidates an intercellular crosstalk mechanism that governs these phenomena.},
}

@article {pmid42801050,
year = {2026},
author = {Youn, BY and Park, S and Song, D and Nam, KC},
title = {Digital twin for neurological conditions: a systematic scoping review.},
journal = {Biomedical engineering letters},
volume = {16},
number = {5},
pages = {1219-1242},
pmid = {42801050},
issn = {2093-985X},
abstract = {Digital twin technology has emerged as a promising approach for advancing precision medicine in complex diseases, particularly in neurology. This scoping review aimed to systematically map the current literature on digital twin applications in neurological conditions, focusing on study characteristics, modeling approaches, data sources, and clinical applications. A comprehensive search across six databases from inception to February 2026 identified 36 studies that met the inclusion criteria. The findings demonstrated a rapid increase in publications since 2023, with Alzheimer's disease (n = 14) and stroke (n = 12) representing the most frequently studied conditions. Data-driven and machine learning-based models were the most common approaches, followed by mechanistic and hybrid models. Major application domains included clinical trial optimization, disease progression modeling, risk prediction, and personalized treatment. However, most studies were proof-of-concept or retrospective in design, with limited external validation and no randomized controlled trials identified. Additionally, many models lacked continuous real-time data integration, indicating that few met the criteria of fully dynamic digital twins. These findings suggest that while digital twins hold substantial potential to transform precision neurology, significant challenges remain in terms of methodological rigor, standardization, and clinical translation. Future research should prioritize prospective validation, integration of multimodal real-world data, and the development of standardized frameworks to support safe and effective implementation.},
}

@article {pmid42801166,
year = {2026},
author = {Wang, Y and Cai, J and Kong, X and Li, J and Ge, Y and Zhang, Y and Chen, Y and Zhu, M and Gong, H and Zhao, D and Pi, J},
title = {Promising Roles of Selenium Nanoparticles in Anti-Tuberculosis Therapy: Opportunities and Challenges.},
journal = {International journal of nanomedicine},
volume = {21},
number = {},
pages = {627381},
pmid = {42801166},
issn = {1178-2013},
mesh = {*Selenium/chemistry/pharmacology/administration & dosage ; Humans ; Animals ; *Tuberculosis/drug therapy ; *Antitubercular Agents/chemistry/pharmacology/administration & dosage ; *Nanoparticles/chemistry ; Mycobacterium tuberculosis/drug effects ; },
abstract = {Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the most threatening infectious disease worldwide. Selenium, an essential micronutrient, is incorporated into selenoproteins such as glutathione peroxidase, which modulate lipid peroxidation and immune responses, thus playing pivotal roles in host defense against infection and control of Mtb dissemination. As an emerging class of selenium-based medicines, selenium nanoparticles (SeNPs) have demonstrated attractive anti-tuberculosis potential based on their favorable bioactivity, lower toxicity compared, high drug-loading capacity, sustained-release kinetics, and enhanced targeting specificity. Beyond their anti-TB potential, SeNPs have shown significant promise in various biomedical applications, including the treatment of diabetes, liver disease, Alzheimer's disease, and cancer, owing to their ability to modulate oxidative stress, inflammation, and apoptotic pathways. This review explores the relationship between selenium and the occurrence and development of tuberculosis, evaluates the potential of serum selenium as an auxiliary diagnostic biomarker, and outlines common preparation methods for SeNPs, including physical, chemical, and biological synthesis approaches. Furthermore, this review systematically summarizes the anti-tuberculosis functions of SeNPs, detailing multiple mechanisms such as accelerating Mtb-lysosome fusion, modulating intracellular ROS levels, driving M1 macrophage polarization, and inhibiting the PI3K/AKT/mTOR signaling pathway to collectively trigger autophagy and apoptosis in Mtb-infected macrophages. These insights may support the development of new anti-tuberculosis technologies based on SeNPs. Furthermore, we also address the key challenges hindering the clinical translation of SeNPs: the long-term in vivo tissue accumulation patterns of SeNPs have not been fully elucidated, long-term systemic nanotoxicity data remain scarce, almost all anti-tuberculosis studies are restricted to in vitro cell experiments and animal models, and the translational pathway from laboratory studies to clinical practice remains ambiguous.},
}

*Selenium/chemistry/pharmacology/administration & dosage
Humans
Animals
*Tuberculosis/drug therapy
*Antitubercular Agents/chemistry/pharmacology/administration & dosage
*Nanoparticles/chemistry
Mycobacterium tuberculosis/drug effects

@article {pmid42801200,
year = {2026},
author = {Liu, R and Yue, H and Li, X and Sun, W and Yang, J},
title = {The Versatile Roles of Exosomes in Neurodegenerative Disorders: From Pathological Mechanism and Diagnostic Biomarkers to Therapeutic Application.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {631482},
pmid = {42801200},
issn = {1177-8881},
mesh = {Humans ; *Exosomes/metabolism/pathology ; *Neurodegenerative Diseases/diagnosis/drug therapy/metabolism/pathology/therapy ; Biomarkers/metabolism/analysis ; Animals ; },
abstract = {Neurodegenerative diseases are characterized by cognitive or motor impairments resulting from the progressive degeneration of neurons or myelin sheaths. Currently, the majority of these disorders remain incurable, leading to significant detriments in patients' quality of life and imposing substantial economic burdens. Exosomes are a type of extracellular vesicles secreted by cells into the extracellular space, typically range from 30 to 150 nanometers in diameter. These vesicles have been identified in a variety of cell types and can participate in various physiological and pathological processes, including intercellular transport of biomolecules, signal transduction, immune modulation, tissue repair, facilitation of tumor metastasis, and evasion of immune surveillance by cancer cells. In recent years, the potential applications of exosomes in neurodegenerative diseases have garnered increasing attention. Their roles encompass early diagnostic biomarker functions, vehicles for drug delivery and therapeutic agents, mediators in the propagation of pathogenic proteins, and regulators of neuroinflammatory responses. In this review, we try to aims to synthesize recent progress in exosome isolation techniques, elucidate the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), and examine the diagnostic and therapeutic applications of exosomes within these conditions. Furthermore, it addresses current limitations in exosome-based applications and explores potential strategies to overcome these challenges. The insights of this review may provide the research directions and guidance for future related researchers in these fields.},
}

Humans
*Exosomes/metabolism/pathology
*Neurodegenerative Diseases/diagnosis/drug therapy/metabolism/pathology/therapy
Biomarkers/metabolism/analysis
Animals

@article {pmid42796101,
year = {2026},
author = {Lee, J},
title = {Blood Amyloid-β Reduction Following Chongnoi-tang Treatment in Alzheimer's Spectrum Conditions: A Retrospective Pilot Observational Study.},
journal = {Journal of clinical medicine},
volume = {15},
number = {18},
pages = {},
pmid = {42796101},
issn = {2077-0383},
abstract = {BACKGROUND/OBJECTIVES: Anti-amyloid immunotherapies reduce amyloid-β (Aβ) plaques but carry a 15-35% risk of amyloid-related imaging abnormalities (ARIA), particularly in APOE ε4/ε4 carriers. This preliminary observational study evaluated blood Aβ oligomer changes following treatment with the multi-component herbal formula Chongnoi-tang (CNT) and contextualized these findings against natural disease trajectories in National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI) reference cohorts.

METHODS: This retrospective pilot cohort included 16 patients with Alzheimer's spectrum conditions treated with CNT. Blood Aβ oligomers were measured using the AlzOn Plus immunoassay. Primary analysis (n = 13) excluded cases with a ceiling-level baseline value, an intercurrent potentially confounding condition, or no true baseline measurement.

RESULTS: Mean blood Aβ oligomer levels decreased by 15.8% ± 13.4% at 6 months (median -20.6%; 95% CI -23.9% to -7.8%; Wilcoxon signed-rank test, p < 0.001; paired Cohen's dz = 1.07). At each participant's final available follow-up, all 13 primary-analysis patients had values below baseline. High-risk patients (n = 4) showed a mean 25.7% reduction. Baseline Aβ level and 6-month percent biomarker change exhibited an exploratory, non-significant inverse trend in the Pearson correlation (r = -0.489, p = 0.090) that was weaker and non-significant in the Spearman sensitivity analysis (ρ = -0.300, p = 0.320), consistent with regression to the mean and mathematical coupling as plausible contributors. Importantly, all four APOE ε4/ε4 homozygotes showed Aβ reductions without ARIA-like clinical events. Mini-Mental State Examination (MMSE) worsening occurred in 37.5% (3/8) of CNT-treated patients versus 42.9% (15/35) in propensity-matched NACC controls (p = 0.89); given the small sample, this comparison is inconclusive.

CONCLUSIONS: In this small, uncontrolled pilot study, CNT was associated with blood Aβ reductions, which should be interpreted as a statistical association rather than confirmed evidence of a treatment effect; no treatment discontinuations due to adverse effects were documented in this small cohort, including among APOE ε4/ε4 carriers. These hypothesis-generating findings warrant further confirmation in prospective randomized controlled trials.},
}

@article {pmid42796281,
year = {2026},
author = {Nguyen, LTH and Nguyen, MT and Nguyen, TU},
title = {Computational Repurposing of Janus Kinase Inhibitors as Potential Therapeutic Candidates for Alzheimer's Disease.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {9},
pages = {},
pmid = {42796281},
issn = {1648-9144},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Janus Kinase Inhibitors/therapeutic use/pharmacology ; *Drug Repositioning/methods ; Molecular Docking Simulation/methods ; Computational Biology/methods ; Signal Transduction/drug effects ; },
abstract = {Background and Objectives: Alzheimer's disease (AD) is the most common neurodegenerative disorder, and current therapies provide only limited symptomatic relief without effectively slowing its progression. Increasing evidence suggests that aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascade contributes to AD-associated neuroinflammation. This study investigated the therapeutic potential and molecular mechanisms of JAK inhibitors in AD using integrated bioinformatics and network pharmacology approaches. Materials and Methods: Potential anti-AD targets of JAK inhibitors were identified using the SwissTargetPrediction and GeneCards databases. Functional enrichment, protein-protein interaction (PPI) analysis, transcriptomic validation using public datasets, regulatory network construction, molecular docking, normal mode analysis (NMA), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction were performed to investigate the potential mechanisms of action of these drugs in AD. Results: Our analysis identified 163 shared targets between JAK inhibitors and AD. Enrichment analysis revealed that these genes were primarily involved in protein phosphorylation and were enriched in key signaling pathways, including the neurotrophin, phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) signaling pathways. PPI analysis identified AKT1, BCL2, SRC, STAT3, and TNF as five highly ranked hub targets across multiple topological algorithms. Transcriptomic validation confirmed significantly higher expression of these targets in the prefrontal cortex of individuals with AD compared with normal subjects. Molecular docking indicated that pacritinib and momelotinib showed relatively favorable predicted interactions with the hub proteins, while NMA revealed differences in the predicted flexibility of the docked complexes. Furthermore, ADMET prediction showed that pacritinib possesses favorable pharmacokinetic properties for the treatment of AD. Conclusions: Collectively, these findings provide mechanistic insights into the potential effects of JAK inhibitors in AD and identify pacritinib as a computationally prioritized candidate that warrants experimental validation in appropriate AD models. However, as this study is based solely on computational analyses without wet-lab validation, the findings should be considered hypothesis-generating in silico evidence, and the potential safety concerns of pacritinib require further investigation.},
}

*Alzheimer Disease/drug therapy
Humans
*Janus Kinase Inhibitors/therapeutic use/pharmacology
*Drug Repositioning/methods
Molecular Docking Simulation/methods
Computational Biology/methods
Signal Transduction/drug effects

@article {pmid42796440,
year = {2026},
author = {Wang, LY and Yeh, SL and Hsu, ST and Huang, SM and Chau, CF and Chuang, CH},
title = {Erinacine C Attenuates Alzheimer's-like Pathology: A Study in APP/PS1 Mice and PC12 Cells.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {18},
pages = {},
pmid = {42796440},
issn = {1420-3049},
support = {109-2637-B-241-004-//National Science and Technology Council/ ; 110-2637-B-241-007-//National Science and Technology Council/ ; },
mesh = {Animals ; PC12 Cells ; *Alzheimer Disease/drug therapy/pathology/metabolism/genetics ; Rats ; Mice ; *Neuroprotective Agents/pharmacology/chemistry ; *Presenilin-1/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Apoptosis/drug effects ; *Amyloid beta-Protein Precursor/genetics/metabolism ; Signal Transduction/drug effects ; Amyloid beta-Peptides/metabolism ; Hippocampus/metabolism/drug effects/pathology ; Hericium/chemistry ; Proto-Oncogene Proteins c-akt/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition and cognitive decline. Clinical evidence indicates that Hericium erinaceus whole fruiting body powder offers limited therapeutic efficacy, which is suggested to be constrained by whole-food matrix interference and uncertainties in central nervous system (CNS) exposure. Therefore, we hypothesized that erinacine C (EC)-a purified active component from Hericium erinaceus mycelia-could resolve these limitations and potentially exhibit favorable neuroprotective effects owing to its low molecular weight and lipophilicity. In this study, we investigated the neuroprotective potential and associated signaling alterations of EC using APP/PS1 transgenic mice and Aβ25-35-induced PC12 cells. In vivo, oral administration of EC alleviated deficits in activities of daily living, as evidenced by improvements in nesting and burrowing behaviors, along with enhanced short-term spatial memory in the Y-maze test. EC treatment was associated with a reduction in hippocampal Aβ plaque accumulation, suppression of glial activation (GFAP and IBA1), and decreased IL-6 levels in both serum and hippocampal tissues. In vitro, EC intervention counteracted Aβ25-35-induced cytotoxicity in PC12 cells. Analysis of signaling markers revealed that EC treatment was accompanied by a restoration of p-Akt/Akt levels and a suppression of p-GSK3β (Tyr216) activation. Consequently, EC treatment was correlated with reduced tau hyperphosphorylation, the up-regulation of the anti-apoptotic protein Bcl-2, and the down-regulation of pro-apoptotic markers including Bax and cleaved-caspase-3, thereby lowering the total apoptotic rate. Taken together, these findings suggest that EC may mitigate cognitive impairment and neurodegeneration in parallel with alterations in the Akt/GSK3β/tau/caspase-3 signaling response, thereby representing a potentially promising therapeutic candidate for the intervention of AD.},
}

Animals
PC12 Cells
*Alzheimer Disease/drug therapy/pathology/metabolism/genetics
Rats
Mice
*Neuroprotective Agents/pharmacology/chemistry
*Presenilin-1/genetics/metabolism
Mice, Transgenic
Disease Models, Animal
Apoptosis/drug effects
*Amyloid beta-Protein Precursor/genetics/metabolism
Signal Transduction/drug effects
Amyloid beta-Peptides/metabolism
Hippocampus/metabolism/drug effects/pathology
Hericium/chemistry
Proto-Oncogene Proteins c-akt/metabolism

@article {pmid42796561,
year = {2026},
author = {Sharma, N and An, SSA},
title = {Small-Molecule NANT Therapeutics Targeting the Brain-Immune Axis in Alzheimer's Disease: Mechanisms, Clinical Progress, and Translational Challenges.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {18},
pages = {},
pmid = {42796561},
issn = {1420-3049},
support = {RS-2021-NR060117//National Research Foundation of Korea/ ; RS-2025-02292973//Korea Institute of Marine Science and Technology Promotion/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology/metabolism ; Animals ; *Brain/drug effects/immunology/metabolism ; Neuroinflammatory Diseases/drug therapy ; *Small Molecule Libraries/therapeutic use/pharmacology ; },
abstract = {Alzheimer's disease (AD) is now widely accepted as a complex disorder involving multiple interconnected pathological processes. Increasing evidence suggest that neuroinflammation and immune system dysregulation actively contribute to neurodegeneration, extending beyond the traditional view that the disease is driven solely by amyloid-β (Aβ) and tau pathology. With the advent of studies showing anti-amyloid antibodies to have only modest effects with significant toxicity, there has been a growing interest in investigating non-amyloid non-tau (NANT) treatment approaches. This review provided a general review of small molecules for neuroinflammation-based NANT therapies in AD. We reviewed several agents that affect the brain/immune axis, namely, kinase inhibitors (nelflamaimod and masitinib), NLRP3 inflammasome inhibitors (MCC950, selnoflast, and dapansutrile), TREM2 activators (VG-3927), gingipain inhibitors, PPARγ activators, KCa3.1 inhibitors, and repurposed drugs such as ambroxol and cromolyn. Some common drawbacks were identified for the drugs that failed to provide their anticipated effects. It was found that they all suffered from late-stage treatment, patient heterogeneity, inadequate central nervous system penetration, and poorly designed preclinical studies. Additional translational challenges included sex-specific differences in neuroimmune responses, APOE ε4-associated immune dysfunction, and the need for biomarker-guided patient selection. Although immune-targeted therapies remain strongly supported by biological evidence in AD, meaningful clinical progress will likely require earlier intervention strategies guided by biomarkers and therapies capable of targeting multiple disease pathways simultaneously.},
}

Humans
*Alzheimer Disease/drug therapy/immunology/metabolism
Animals
*Brain/drug effects/immunology/metabolism
Neuroinflammatory Diseases/drug therapy
*Small Molecule Libraries/therapeutic use/pharmacology

@article {pmid42797041,
year = {2026},
author = {Hailati, S and Yasheng, Y and Yin, Y and Jiang, C and Liu, Y and Ding, W and Dilimulati, D and Baishan, A and Paerhati, Y and Aikebaier, A and Dolkun, A and Zhou, W},
title = {Multi-Component Xinjiang Basil Essential Oil Mitigates Alzheimer's Disease-like Pathology Through Amyloid and Neuroinflammatory Modulation.},
journal = {Nutrients},
volume = {18},
number = {18},
pages = {},
pmid = {42797041},
issn = {2072-6643},
support = {2025D01E32//Natural Science Foundation for Distinguished Young Scholars of Xinjiang Uygur Autonomous Region/ ; 2025D01C329//Natural Science Foundation for Young Scholars of Xinjiang Uygur Autonomous Region/ ; 2022TSYCCX0035//Tianshan Talents-Youth Science and Technology Innovation Talents Training Program of Xinjiang Uygur Autonomous Region/ ; XJDX1713//Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology/ ; 2023//Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices/ ; 2023//Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Oils, Volatile/pharmacology/isolation & purification ; Mice ; *Neuroprotective Agents/pharmacology ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *Ocimum basilicum/chemistry ; Male ; Mice, Transgenic ; Brain/metabolism/drug effects ; *Neuroinflammatory Diseases/drug therapy ; NF-kappa B/metabolism ; *Plant Oils/pharmacology ; Signal Transduction/drug effects ; NF-KappaB Inhibitor alpha/metabolism ; },
abstract = {Background: Basil (Ocimum basilicum L.) is a herbaceous plant belonging to the family Lamiaceae. It is not only edible, but it also has nutritional value and can be used for medicinal purposes. Previous studies suggest that basil-derived extracts may protect neurons from injury. Objectives: Our research aimed to investigate whether basil essential oil (BEO) from Xinjiang has a neuroprotective effect in Alzheimer's disease (AD)-like pathological mouse model and to elucidate the mechanism underlying this effect. Methods: The essential oil was extracted using steam distillation. UHPLC-MS/MS technology was used to identify constituents detected in brain tissue following intranasal administration. In the experiment, BEO was administered intranasally to APP/PS1 mice for 4 weeks, and its therapeutic effects on AD-like pathological features were evaluated through behavioral and biochemical assessments. Results: The results showed that there were 787 compounds in the BEO, of which 30 putatively annotated compounds were detected in brain tissue after intranasal administration. Most of these were prenol lipids (36%). BEO markedly enhanced spatial learning and cognitive abilities in APP/PS1 mice, while also reducing neurodegeneration within the hippocampus and decreasing Aβ1-40 and Aβ1-42 levels. BEO additionally lowered the levels of IL-1β, IL-6, and TNF-α and inhibited the activation of astrocytes and microglia. BEO exerted its neuroprotective effects by reducing the activation of the IκB-α/NF-κB pathway. Conclusions: BEO exerted neuroprotective-like effects in this AD mouse model accompanied by anti-inflammatory activity and suppression of amyloid-β (Aβ) accumulation, and BEO treatment was associated with reduced IκB-α/NF-κB pathway activation. This research demonstrated that BEO might serve as a natural treatment against AD.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism
*Oils, Volatile/pharmacology/isolation & purification
Mice
*Neuroprotective Agents/pharmacology
*Amyloid beta-Peptides/metabolism
Disease Models, Animal
*Ocimum basilicum/chemistry
Male
Mice, Transgenic
Brain/metabolism/drug effects
*Neuroinflammatory Diseases/drug therapy
NF-kappa B/metabolism
*Plant Oils/pharmacology
Signal Transduction/drug effects
NF-KappaB Inhibitor alpha/metabolism

@article {pmid42797331,
year = {2026},
author = {Zeng, W and Zhou, D and Wang, T and Ma-Högemeier, ZL and Cai, S and Liu, B and Song, C and Guo, L and Zhai, R and Song, X and He, Z and Dong, Y},
title = {Manganese Dioxide Nanoparticles Protect PC12 Cells Against H2O2-Induced Oxidative Stress Injury by Regulating PI3K/Akt-Mediated Autophagy.},
journal = {Pharmaceutics},
volume = {18},
number = {9},
pages = {},
pmid = {42797331},
issn = {1999-4923},
support = {JCYJ20240813113330039//Shenzhen Science and Technology Innovation Commission/ ; 2023KTSCX126//Natural Science Foundation of Education Department of Guangdong Province/ ; 202305AF150139//Natural Science Foundation of Yunnan Province Science and Technology Department/ ; YSZJGZZ-2021083//Natural Science Foundation of Yunnan Province Science and Technology Department/ ; },
abstract = {Background: Oxidative stress-mediated neuronal injury is critically involved in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Manganese dioxide (MnO2), owing to its intrinsic reactive oxygen species (ROS)-scavenging capacity, has emerged as a promising neuroprotective candidate; however, the underlying molecular mechanisms remain insufficiently defined. Methods: Bovine serum albumin-templated MnO2 nanoparticles (BSA-MnO2 NPs) were synthesized, and their protective effects were evaluated in H2O2-treated PC12 cells. Results: BSA-MnO2 NPs significantly inhibited H2O2-induced reductions in cell viability, ROS overproduction, and mitochondrial membrane potential disruption. Mechanistically, H2O2 increased both LC3-II and p62 levels, indicating impaired autophagic flux. Activation of autophagy by serum starvation alleviated H2O2-induced injury, whereas chloroquine exacerbated cellular damage and abolished the protective effects of BSA-MnO2 NPs, suggesting that the restoration of autophagy contributes to BSA-MnO2 NPs-mediated neuroprotection. Further analysis showed that BSA-MnO2 NPs enhanced Akt phosphorylation, while LY294002, a PI3K inhibitor, suppressed Akt activation, disrupted autophagy regulation, and eliminated their neuroprotective effects. In contrast, chloroquine did not affect Akt phosphorylation, indicating that PI3K/Akt signaling acts upstream of autophagy regulation. Conclusions: Collectively, these findings demonstrate that BSA-MnO2 NPs protect PC12 cells against H2O2-induced oxidative injury by restoring autophagy through the PI3K/Akt signaling pathway, highlighting a potential role of BSA-MnO2 NPs in the treatment of oxidative-stress-related neurodegenerative disorders.},
}

@article {pmid42797432,
year = {2026},
author = {Zhou, Y and Liu, B and Wang, H and Cao, L},
title = {Two-Dimensional MXene-Loaded Butylphthalide Enhances the Treatment of Alzheimer's Disease by Inhibiting Ferroptosis and Oxidative Stress.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
pmid = {42797432},
issn = {1424-8247},
support = {23XD1402500//Shanghai Outstanding Academic Leaders/ ; },
abstract = {Introduction: Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder involving ROS and ferroptosis. MXene, a 2D material, functions as both a drug carrier and ROS scavenger. Butylphthalide (NBP), a neuroprotective agent, suffers from poor aqueous solubility and bioavailability. This study synthesized Ti2C@BSA-NBP, a novel MXene nanocomposite, to enhance NBP delivery and therapeutic efficacy for AD. Materials and Methods: Ti2C@BSA-NBP was synthesized via self-assembly and amidation reaction, and characterized by multiple techniques. In vitro, ROS-scavenging capacity, mitochondrial function, and ferroptosis markers were assessed in H2O2-injured cells. In vivo efficacy was evaluated in an AD mouse model via behavioral, histopathological, and biochemical analyses. Results: The nanocomposite exhibited robust ROS-scavenging activity in vitro, significantly attenuating ROS, restoring mitochondrial function, and reversing ferroptosis markers. In vivo, Ti2C@BSA-NBP ameliorated learning/memory deficits, partially repaired neuronal morphology, and suppressed neuroinflammation. Mechanistically, it downregulated ACSL4 and Aβ overexpression while restoring GPX4 inhibition. Discussion: Ti2C@BSA-NBP exerts synergistic neuroprotection through MXene-mediated ROS clearance and NBP-mediated multi-target regulation, counteracting oxidative stress, ferroptosis, and neuroinflammation. Conclusions: Ti2C@BSA-NBP is a promising multifunctional nanoplatform integrating antioxidant activity, enhanced drug delivery, and ferroptosis modulation for AD therapy.},
}

@article {pmid42794721,
year = {2026},
author = {Velázquez De Castro-Bono, A and Castro-Luna, G and Guil-Guerrero, JL},
title = {Reframing Alzheimer's Disease Through a Redox-Metabolic Framework.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
pmid = {42794721},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; Oxidation-Reduction ; Animals ; Mitochondria/metabolism ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Glucose/metabolism ; Signal Transduction ; Brain/metabolism/pathology ; Energy Metabolism ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) has been conceptualised as a proteinopathy driven by amyloid-β plaques and hyperphosphorylated tau neurofibrillary tangles. AD should not be understood as exclusively a proteinopathy or a metabolic/redox disorder, but as a network of interacting processes in which metabolic dysfunction, mitochondrial impairment, redox dysregulation, amyloid-β, tau, neuroinflammation, metal dyshomeostasis, and regulated cell death reinforce one another. This review examines AD through a redox-metabolic framework integrating cerebral glucose metabolism, insulin signalling, mitochondrial bioenergetics, metal homeostasis, and regulated cell death. We discuss how glucose hypometabolism, impaired oxidative phosphorylation, and weakened antioxidant defences may promote reactive oxygen species production and self-reinforcing oxidative and metabolic dysfunction. We examine interactions with amyloid-β and tau pathology, glial immunometabolism, gut-brain signalling, neuroinflammation, and metal-mediated toxicity. Advances in multi-omics, blood-based metabolomic and lipidomic biomarkers, and imaging may enable earlier biological stratification. Therapeutic strategies targeting mitochondria, NRF2 signalling, metabolic dysfunction, metal dyshomeostasis, and regulated oxidative cell death are evaluated based on current evidence and their potential complementarity with amyloid-directed therapies. Although temporal relationships remain unresolved, redox-metabolic dysfunction may represent an early determinant and amplifier of neuronal vulnerability. Evidence for lecanemab and donanemab supports an integrative rather than replacement model of AD treatment. This framework may facilitate earlier diagnosis, patient stratification, and complementary disease-modifying interventions.},
}

Humans
*Alzheimer Disease/metabolism/pathology
Oxidation-Reduction
Animals
Mitochondria/metabolism
Oxidative Stress
Amyloid beta-Peptides/metabolism
Glucose/metabolism
Signal Transduction
Brain/metabolism/pathology
Energy Metabolism
tau Proteins/metabolism

@article {pmid42794742,
year = {2026},
author = {Law, AD and Brandes, M and Bollen, M and Soumyanath, A and Kretzschmar, D},
title = {Withania somnifera (Ashwagandha) Improves Fitness in Aged Drosophila by Reducing AKT Phosphorylation.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
pmid = {42794742},
issn = {1422-0067},
support = {5U19AT010829-24/NH/NIH HHS/United States ; },
mesh = {Animals ; *Withania/chemistry ; Phosphorylation/drug effects ; *Proto-Oncogene Proteins c-akt/metabolism ; *Drosophila melanogaster/drug effects/metabolism ; *Aging/drug effects ; *Plant Extracts/pharmacology/chemistry ; Signal Transduction/drug effects ; *Drosophila Proteins/metabolism ; Longevity/drug effects ; TOR Serine-Threonine Kinases/metabolism ; },
abstract = {With increasing global life expectancy, there is a growing need for strategies to mitigate age-related declines in fitness and health. Withania somnifera (WS), commonly known as ashwagandha, has been traditionally recognized by ayurvedic medicine for its benefits in promoting healthy aging. More recently, it has also emerged as a potential treatment option for age-related diseases such as Alzheimer's disease (AD), Parkison's disease, and Huntington's disease. WS has been shown to improve sleep quality, has adaptogenic and antioxidant properties, and enhances exercise performance by improving muscle strength and recovery. However, the molecular mechanisms underlying the effects of WS on aging are poorly understood. Therefore, we used Drosophila melanogaster flies to assess the impact of analytically characterized water (WSAq) extracts of WS root. To test effects during aging, the flies were treated at middle-age (4 weeks from eclosion) for two weeks. We found that WSAq reduced Akt phosphorylation in fly heads and that Akt is required to improve fitness in the fast phototaxis assays. We also determined that the effects of WSAq treatment depended on the Akt downstream pathways Tsc/mTOR, FOXO, and NRF. This supports that WS provides resilience to the age-related decline in fitness by modifying Akt signaling and affecting downstream pathways connected to aging and longevity.},
}

Animals
*Withania/chemistry
Phosphorylation/drug effects
*Proto-Oncogene Proteins c-akt/metabolism
*Drosophila melanogaster/drug effects/metabolism
*Aging/drug effects
*Plant Extracts/pharmacology/chemistry
Signal Transduction/drug effects
*Drosophila Proteins/metabolism
Longevity/drug effects
TOR Serine-Threonine Kinases/metabolism

@article {pmid42795418,
year = {2026},
author = {Merino, JJ and Rodríguez-Arellano, JJ and Busquets, X and Flores, AI and Toledano, A},
title = {Comparative Analysis of Plasma Biomarkers of Alzheimer's Disease and Frontotemporal Dementia: The Dual Role of Soluble Fractalkine as a Biomarker of Frontotemporal Dementia and Its Neuroprotective Effects in Cortical Neurons "In Vitro".},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {9},
pages = {},
pmid = {42795418},
issn = {2075-1729},
support = {RYC-2006- 002658//Ministerio de Ciencia y Tecnología (Ramon and Cajal program)/ ; },
abstract = {Frontotemporal lobar degeneration (FTD) and Alzheimer's disease (AD) are proteinopathies characterized by the abnormal accumulation and aggregation of specific proteins like Aβ-42 deposits, p-tau accumulation, and abnormal cytosolic aggregation of TAR DNA-binding protein 43 (TDP-43) in FTD patients. Recently, the identification of neuroinflammatory mediators as predictors of cognitive decline has gained attention. We have compared several plasma biomarkers of cognitive impairment between AD and FTD patients using Enzyme-Linked Immunosorbent Assay (ELISA) (pg/mL), including CX3CR1 and soluble fractalkine (sFK, also termed CX3CL1), TDP-43, neurofilament light chain M (NfL M), p-tau217, and GFAP (glial fibrillary acidic protein). Chemokines are HIV-1 co-receptors that facilitate the spread of HIV-1 infection and induce apoptosis in the brain. Whilst these chemokines promote neuronal survival and regulate neuron-glia interactions, they also contribute to neurodegeneration. Fractalkine, also known as CX3CL1, is a delta chemokine that binds to its CX3CR1 chemokine receptor. As a membrane isoform, fractalkine can be released in a soluble form by damaged neurons under either inflammatory and/or excitotoxic conditions; since neuroinflammation contributes to neurodegeneration and dementia, we compared these CX3CR1/sFK delta chemokine levels in seropositive patients (with suppressed viral loads) and without neurodegeneration to age-matched controls. This was done in order to study whether inflammation could upregulate these chemokines in the absence of cognitive impairment. To our knowledge, this is the first study showing that increased plasma levels of CX3CR1 and soluble fractalkine could be associated with FTD pathology as compared to control subjects (without neurodegeneration). However, peripheral NfL M, GFAP, and p-tau217 levels did not differ between AD and FTD patients. Post-mortem analysis of human FTD brains revealed anatomical changes, including hippocampal involution and tau deposits. Given that soluble fractalkine can contribute to cognitive impairment while also exerting protective effects against brain insults, we did an additional (independent experiment) in cortical neurons in vitro under LPS-induced neurotoxicity. We confirmed that adding recombinant fractalkine for 24 h prevented lipopolysaccharide (LPS)-induced apoptosis in cortical neurons at 7 days in vitro (DIV); moreover, twenty-four hours after LPS treatment, sFK prevented neuronal apoptosis by decreasing caspase-3 activity and exerted neuroprotective effects against inflammation. Our findings suggest that fractalkine mitigates LPS-induced neuronal injury by limiting apoptosis and inflammatory responses. Furthermore, our findings suggest for the first time that elevated circulating sFK levels may indirectly be associated with FTD pathology as compared to healthy controls. However, sFK could also reflect compensatory protective responses to neuronal injury.},
}

@article {pmid42784125,
year = {2026},
author = {Demir, ÜF and Karakuş Dilbaz, F},
title = {Anti-Amyloid Monoclonal Antibodies in Early Alzheimer Disease: Lecanemab and Donanemab.},
journal = {Neurology international},
volume = {18},
number = {9},
pages = {},
doi = {10.3390/neurolint18090171},
pmid = {42784125},
issn = {2035-8385},
abstract = {BACKGROUND/OBJECTIVES: Alzheimer disease (AD) causes progressive cognitive and functional loss and substantial caregiver and healthcare burden. Anti-amyloid monoclonal antibodies represent a shift toward biology-directed treatment in biomarker-confirmed early symptomatic AD, but modest clinical effects must be balanced against amyloid-related imaging abnormalities (ARIA), intensive monitoring, and implementation burden. Heterogeneity in trial populations, endpoints, dosing, stopping rules, and follow-up complicates interpretation. This narrative review critically integrates efficacy, safety, durability, biomarker, and implementation evidence for lecanemab and donanemab while preserving study-family relationships and avoiding unsupported cross-trial superiority claims.

METHODS: For this revised narrative review, a targeted PubMed/MEDLINE search covering the period from database inception was initially conducted before manuscript submission and was subsequently updated through 21 August 2026, supplemented by reference-list and citation tracking. Search terms combined Alzheimer disease with lecanemab, donanemab, anti-amyloid monoclonal antibody, ARIA, APOE, amyloid PET, open-label extension, real-world, clinical meaningfulness, implementation, and access. Sixty-two sources were purposively selected for a comprehensive narrative synthesis; no meta-analysis or formal certainty grading was performed.

RESULTS: Pivotal trials demonstrated statistically significant but modest average slowing of decline: Clarity AD showed a 0.45-point between-group difference in CDR-SB worsening at 18 months, and TRAILBLAZER-ALZ 2 showed a 3.25-point iADRS difference in the low/medium-tau population at 76 weeks. ARIA-E occurred in 12.6% of lecanemab-treated and 24.0% of donanemab-treated participants in the pivotal trials, with higher risk in APOE ε4 carriers. Extensions and biomarker analyses suggest persistent biological effects but are less secure for causal inference, and real-world evidence is currently more mature for lecanemab.

CONCLUSIONS: Both antibodies substantially reduce amyloid and modestly slow average clinical decline in selected patients, but neither restores lost function, greater amyloid clearance does not establish greater individual benefit, and cross-trial superiority cannot be inferred. Treatment requires biomarker-guided selection, APOE-informed risk counseling, serial MRI, infusion and ARIA-management capacity, and shared decision-making that incorporates cost, access, and patient/caregiver burden.},
}

@article {pmid42784228,
year = {2026},
author = {Zingler, G and Herdegen, T},
title = {In Patients Experiencing Pain and Inflammation, the Use of Non-Steroidal Anti-Inflammatory Drugs Is More Likely a Marker of the Observed Cardiovascular Risk Rather than Its Cause: A Viewpoint.},
journal = {Pharmacy (Basel, Switzerland)},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/pharmacy14060139},
pmid = {42784228},
issn = {2226-4787},
abstract = {Non-steroidal anti-inflammatory drugs (NSAIDs) have been among the most frequently prescribed medications worldwide for several decades. Ongoing vigilance regarding their potential adverse effects on the gastrointestinal tract and kidneys remains critical. Over the past twenty years, accumulating evidence has indicated an increased cardiovascular (CV) risk associated with NSAID use, posing a significant challenge for both patients and healthcare providers. This issue has prompted the US Food and Drug Administration (FDA) to issue explicit warnings concerning NSAID use. Recent data and comparative analyses of existing publications provide a basis for critically re-evaluating the association between NSAID use and potential CV risk, particularly when NSAIDs are administered for approved indications such as the treatment of pain and inflammation in patients with arthritis. The debate regarding the CV safety of NSAIDs centers on establishing causality. It is necessary to determine whether NSAIDs directly induce CV risks by initiating new pathological processes or act as modulators that influence the severity of pre-existing susceptibilities. The evidence presented in this review supports the view that NSAIDs do not create new CV risks but reduce CV incidents in patients with inflammatory pathologies such as arthritis. Conversely, NSAIDs have been observed to slightly increase CV risk when used at inappropriate high doses or in patients without inflammatory pain, such as those with Alzheimer's disease or other vulnerable populations. This perspective shifts the focus from causality to context-based risk management. The distinction between risk generation and risk modulation is proposed as a framework for the rational use of NSAIDs. The potential for NSAIDs to exacerbate pre-existing CV risk is dependent on the context of morbidity, and is low when used for anti-inflammatory indications in populations with the highest benefit, i.e., those with inflammatory morbidities. A general condemnation of NSAIDs keeps relevant patient populations from the only anti-inflammatory analgetic pharmacotherapy so far available.},
}

@article {pmid42784819,
year = {2026},
author = {Barak, Y and Cheer, SM and Mullen, R},
title = {Oil on the brain: dementia in the popular press prior to the 1906 Alzheimer case report.},
journal = {The New Zealand medical journal},
volume = {139},
number = {1642},
pages = {15-20},
doi = {10.26635/6965.7443},
pmid = {42784819},
issn = {1175-8716},
mesh = {Humans ; New Zealand ; History, 19th Century ; *Newspapers as Topic/history ; *Dementia/history/etiology ; History, 20th Century ; *Alzheimer Disease/history ; },
abstract = {BACKGROUND AND AIMS: Concepts of dementia precede the description published by Alzheimer. Historically, the term was misunderstood and misused by the published newspapers of the nineteenth century. We aimed to describe the historical use of the term dementia in New Zealand newspapers.

METHOD: Papers Past is a project of the National Library of New Zealand that aims to digitise all New Zealand newspapers from 1839 onwards. There are 96,022,840 newspaper articles in this dataset.

RESULTS: There were 1,521 newspaper articles between 1839 and 1906 in which the word dementia appeared in the content or title. Of these, 165 met the inclusion criteria. Of included articles, 87 had a description of the condition, 92 mentioned a cause of dementia and 25 included a description of management. Categories were not mutually exclusive. The common cause of dementia described was mental impairment (N=44), with special emphasis on mania, postpartum depression and intellectual disability. This was followed by environmental factors (N=34) and alcohol use (N=26). The common form of management for dementia was incarceration within an asylum or a gaol, occurring in 18 of 25 reported cases. Specific treatments for dementia included: a blister to the neck, rheumatic balsam, milk with lime water, marine serum and cranial surgery.

CONCLUSION: The descriptions of dementia from newspaper articles were consistent with nineteenth century Western concepts of the disease, and the causes and treatment of dementia reflected the New Zealand environment and Pākehā culture during colonial times.},
}

Humans
New Zealand
History, 19th Century
*Newspapers as Topic/history
*Dementia/history/etiology
History, 20th Century
*Alzheimer Disease/history

@article {pmid42785112,
year = {2026},
author = {Cummings, JL and Scheltens, P},
title = {Evoke (+) trials of semaglutide for early alzheimer's disease: Innovations, lessons, and implications.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100677},
doi = {10.1016/j.tjpad.2026.100677},
pmid = {42785112},
issn = {2426-0266},
abstract = {The evoke and evoke+ trials for the treatment of early Alzheimer's disease (AD) with semaglutide were founded on the observation that semaglutide reduced the incidence of dementia in patients with type 2 diabetes. Non-clinical investigations support an effect of semaglutide on AD pathology. The evoke and evoke+ trials were large, well conducted, and innovative. These trials were negative, showing no clinical benefit of treatment with 14 milligrams of semaglutide for two years. Semaglutide produced a statistically significant and robust reduction in high sensitivity C-reactive protein consistent with suppression of peripheral inflammation. There was no effect on most plasma measures collected. CSF analyses showed nominally significant effects on biomarkers of the core biology of AD; YKL-40 and glial fibrillary acidic protein in CSF were decreased indicating a reduction in astroglial activation. The magnitude of these changes was small (7%-10%) and there was no correlative effect on AD progression. The discrepancy between observations in real world data and the trial outcomes indicates that treatment of symptomatic AD confirmed with biomarkers differs from treatment of patients with diabetes who were cognitively unimpaired and at risk for all cause cognitive decline. The evoke and evoke+ trials suggest that reduction in peripheral inflammation may be insufficient to produce beneficial clinical effects in AD. The results of the evoke(+) trials do not exclude the possibility that AD populations enriched for elevated levels of markers of peripheral inflammation or use of brain penetrant GLP-1 RAs could produce therapeutic benefit.},
}

@article {pmid42785177,
year = {2026},
author = {Mizukami, N and Miwa, K and Umeda, K and Fukuda, T and Takano, N and Hiramoto, M},
title = {Prohibitin 2 mediates the mitochondrial protective effect of the whey-derived tetrapeptide Gly-Thr-Trp-Tyr.},
journal = {Biochemical and biophysical research communications},
volume = {837},
number = {},
pages = {154609},
doi = {10.1016/j.bbrc.2026.154609},
pmid = {42785177},
issn = {1090-2104},
abstract = {Certain dairy products have been reported to reduce the risk of cognitive decline in older adults and patients with Alzheimer's disease (AD). Intake of the whey-derived tetrapeptide Gly-Thr-Trp-Tyr (GTWY) improves mild cognitive impairment in healthy adults, while GTWY administration in mice suppresses AD-like pathologies, including amyloid-beta (Aβ) accumulation and neuroinflammation. GTWY treatment also reduces Aβ-induced mitochondrial dysfunction in neuronal cells. However, the molecular mechanisms underlying these effects remain unclear. Here, we identified prohibitin 2 (PHB2) as a direct binding partner of GTWY in human neuroblastoma SH-SY5Y cells and investigated its role in the mitochondrial protective effect of GTWY. GTWY treatment increased the abundance of the prohibitin complex detected by blue native PAGE without affecting PHB1 or PHB2 expression. Moreover, PHB2 knockdown abolished the mitochondrial protective effect of GTWY, indicating that PHB2 mediates this effect. These findings suggest that GTWY binding to PHB2 modulates the functional state of the prohibitin complex, thereby preserving mitochondrial function. Our results provide new insights into the molecular mechanisms underlying the mitochondrial protective effects of whey-derived peptides and highlight the potential role of the prohibitin complex in mediating these effects.},
}

@article {pmid42785333,
year = {2026},
author = {Mu, R and Hofmann, A and Gong, K and Liu, M and Roussak, A and Lowery, J and Chen, Y and Paczynski, M and Posey, Z and Cheng, Y and Xu, Y and Xie, Y and Powell, WJB and Oh, I and Gupta, A and Sykora, N and Budde, J and Funk, S and Benzinger, TLS and Holtzman, DM and Morris, JC and Snider, BJ and Bateman, RJ and Schindler, SE and Cruchaga, C},
title = {Dynamic changes in plasma biomarkers of Alzheimer's disease in patients treated with lecanemab: a longitudinal cohort study.},
journal = {The Lancet. Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1016/S1474-4422(26)00284-X},
pmid = {42785333},
issn = {1474-4465},
abstract = {BACKGROUND: Anti-amyloid antibodies slow cognitive and functional decline in individuals with early symptomatic Alzheimer's disease, but few studies have examined changes associated with these treatments in plasma biomarkers linked to neurodegeneration. We analysed changes in a panel of 130 plasma proteins and their associations with conversion to amyloid PET negative status and cognitive changes in patients receiving lecanemab infusions as part of their clinical care.

METHODS: This longitudinal cohort study included patients with early symptomatic Alzheimer's disease and positive amyloid biomarkers who were identified as candidates for biweekly lecanemab infusions based on the US Food and Drug Administration label and consented to blood collection at the Washington University Memory Diagnostic Center (St Louis, MO, USA) between July 17, 2023, and Oct 10, 2025. Lecanemab was administered as a 10 mg/kg intravenous infusion every 2 weeks. Patients underwent clinical assessments and blood draws approximately every 6 months over up to 2 years. Research participants enrolled at the Knight Alzheimer Disease Research Center (Knight ADRC; St Louis, MO, USA) between May 3, 1996, and Feb 27, 2025, and who did not receive anti-amyloid antibodies, were included as control groups (an amyloid β-negative [Aβ-] group without cognitive impairment and an untreated group with cognitive impairment). The primary outcome was change in plasma concentrations of protein biomarkers associated with Alzheimer's disease pathology with lecanemab treatment. Associations between plasma biomarker changes and number of lecanemab infusions were examined using regression and mixed-effects models, with adjustment for demographics.

FINDINGS: The study included 197 patients in whom lecanemab infusions had been started (lecanemab group), as well as 173 patients in whom lecanemab had been ordered but not yet started, who were combined with 1139 research participants with cognitive impairment from the Knight ADRC cohort to form the untreated control group with cognitive impairment (n=1312). An additional 458 research participants formed the Aβ- control group without cognitive impairment. In the lecanemab group, the median patient age was 73 years (IQR 69-77); 104 (53%) were female and 93 (47%) were male; and most participants were White (187 [98%] of 190 with available data) and non-Hispanic (183 [97%] of 188 with available data). 130 biomarkers were classified into four distinct trajectories, with 34 showing significant changes (false discovery rate <0·05) in the lecanemab group. The trajectories were: normalising, with biomarkers shifting towards concentrations found in Aβ-individuals without cognitive impairment (eg, phosphorylated tau [p-tau]217, MAPT, and GFAP); overcorrecting, with biomarkers shifting towards and then beyond concentrations found in Aβ- individuals without cognitive impairment (eg, amyloid β peptides); opposite, with biomarkers shifting further from concentrations found in Aβ- individuals without cognitive impairment (eg, NPTXR, NRGN, and TREM2); and unchanged (eg, NEFL and APOE).

INTERPRETATION: Lecanemab treatment was associated with dynamic, multidirectional changes across plasma biomarkers of Alzheimer's disease pathology, with partial normalisation of amyloid and tau biomarkers alongside abnormal concentrations of inflammatory and neurodegeneration-related biomarkers (eg, TREM2 and NPTXR), which might reflect an immune response to amyloid plaques and effects of treatment on neuronal and synaptic processes distinct from amyloid clearance. These divergent trajectories suggest that different biomarkers could eventually serve different clinical purposes, such as monitoring treatment response or informing patient prognosis, although further validation is needed.

FUNDING: National Institute on Aging, Cure Alzheimer's Fund, and Washington University.},
}

@article {pmid42785896,
year = {2026},
author = {Priya, and Mittal, R and Banerjee, J and Dixit, A},
title = {Blood-based biomarkers in Alzheimer's and Parkinson's disease: From molecular pathology to therapeutic potential.},
journal = {International review of neurobiology},
volume = {191},
number = {},
pages = {225-273},
doi = {10.1016/bs.irn.2026.02.006},
pmid = {42785896},
issn = {2162-5514},
mesh = {Humans ; *Parkinson Disease/blood/therapy/pathology ; *Biomarkers/blood ; *Alzheimer Disease/blood/pathology/therapy ; *alpha-Synuclein/blood ; Animals ; Amyloid beta-Peptides/blood ; Pathology, Molecular ; tau Proteins/blood ; },
abstract = {Alzheimer's (AD) and Parkinson's disease (PD) represent a major class of neurodegenerative disorders characterized by different proteinopathies with amyloid-β plaques and tau tangles in AD, while α-synuclein containing Lewy bodies in PD, specific molecular signatures. Alongside this central mechanism, they share pathological cascades including axonal degeneration, synaptic dysfunction, glial activation and neuroinflammation. The emergence of blood-based biomarkers, represents a paradigm shift in the field of diagnosis and therapeutics by addressing these core pathological mechanism of central nervous system. This chapter highlights a overview of blood-based biomarkers emerging in the field of AD and PD, exploring the clinical utility of core pathology markers (Aβ42/40, p-tau species, and α-synuclein), alongside other neurodegenerative markers such as neurofilament light chain and glial activation markers like GFAP. Beyond the diagnosis, we emphasize on the potential role of blood-based biomarkers as a surrogate and pharmacodynamic endpoint in disease modifying clinical trial development, facilitating dose optimization and target engagement. Future prospects empathize on the use of multimodal approach integration, trajectory modeling and novel target discovery. Collectively, these blood-based biomarkers enable transition of neurodegenerative disorders treatment from symptom-based classification to towards a mechanism targeted therapeutic framework.},
}

Humans
*Parkinson Disease/blood/therapy/pathology
*Biomarkers/blood
*Alzheimer Disease/blood/pathology/therapy
*alpha-Synuclein/blood
Animals
Amyloid beta-Peptides/blood
Pathology, Molecular
tau Proteins/blood

@article {pmid42785901,
year = {2026},
author = {Rajesh, N and R, J and Joji, R and Sivakumar, S and Francis, D},
title = {Neurofilament light chain (NfL) as a biomarker for neurodegeneration: Protein biology, detection methods, and clinical applications.},
journal = {International review of neurobiology},
volume = {191},
number = {},
pages = {447-485},
doi = {10.1016/bs.irn.2026.05.009},
pmid = {42785901},
issn = {2162-5514},
mesh = {Humans ; Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Neurofilament Proteins/metabolism ; Animals ; *Intermediate Filaments/metabolism ; },
abstract = {Neurofilaments are vital structural components of neurons and play a central role in preserving axonal architecture and function. Among these, neurofilament light chain (NfL) has emerged as a sensitive biomarker of neuroaxonal injury. This chapter delineates the molecular organisation of neurofilaments, tracing their hierarchical assembly from coiled-coil dimers to mature filaments, and emphasises their contribution to axonal stability, calibre regulation, and intracellular transport. It further examines how perturbations in neurofilament homeostasis reflect neuronal damage across a broad spectrum of neurological disorders. Advances in analytical technologies, particularly ultrasensitive immunoassays such as Sioma and ELISA, have enabled robust quantification of NfL in cerebrospinal fluid and blood, facilitating its translation from experimental research into clinical practice. The diagnostic and prognostic relevance of NfL is examined across neurodegenerative, inflammatory, traumatic, and vascular diseases of the nervous system, with particular focus on Alzheimer's and Parkinson's diseases, highlighting its utility for disease monitoring and assessing treatment response. A discussion of clinical factors to consider when assessing NfL for disease diagnosis, along with its current challenges, is provided to draw attention to additional research. Through mechanistic insights spanning protein biology, clinical findings, and biomarker science, this chapter highlights NfL as a robust and non-invasive indicator of neuroaxonal injury applicable across distinct aetiologies. It posits that the systematic incorporation of NfL measurements into clinical workflows may refine nosological classification, enhance diagnostic and prognostic precision, and improve risk stratification at both individual and cohort levels, whilst informing evidence-based therapeutic decision-making and longitudinal patient management across a wide spectrum of neurological conditions.},
}

Humans
Biomarkers/metabolism
*Neurodegenerative Diseases/diagnosis/metabolism
*Neurofilament Proteins/metabolism
Animals
*Intermediate Filaments/metabolism

@article {pmid42785906,
year = {2026},
author = {Eliazer, GR and Kandasamy, M},
title = {Circulating biochemical signatures of neurodegeneration in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {191},
number = {},
pages = {91-111},
doi = {10.1016/bs.irn.2026.06.004},
pmid = {42785906},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; *tau Proteins/blood ; *Amyloid beta-Peptides/blood ; Animals ; },
abstract = {Alzheimer's Disease (AD), a major cause of progressive memory loss, is pathogenically associated with the accumulation of amyloid-beta (Aβ) plaques, tau-mediated neurofibrillary tangles, neuroinflammation, and neurodegeneration. The molecular, biochemical and cellular malformation apears to occur before the onset of behavioural symptoms and intensifies as the disease progresses, highlighting the importance of early diagnostic approaches. The routine neuroimaging-based techniques, such as magnetic resonance imaging and positron emission tomography, are highly valuable to monitor the emergence of symptoms but are limited by high cost and accessibility. The cerebrospinal fluid-based methods provide valuable insight into the state of disease, however the procedure associated with sample collection is highly invasive. Eventually, the blood-based biomarkers have emerged as a promising and minimally invasive alternative procedure for the detection and monitoring of AD. The circulating biomarkers such as Aβ , phosphorylated tau isoforms, and associated abnormal biochemical signatures are correlated with pathological processes in AD. Assessing these blood biomarkers is not only crucial for diagnostics but also important for monitoring the changes associated with treatment in AD. As most current treatment options provide only symptomatic relief, advanced diagnostic approaches are essential for early detection and therapeutic intervention. The blood-based biomarkers represent a transformative step toward early diagnosis, large-scale screening, and precision medicine in AD, with significant potential for the development of disease-modifying therapies. Thus, this book chapter provides an overview of blood-based biomarker panels and discusses recent advances in bioanalytical technologies in AD.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
*tau Proteins/blood
*Amyloid beta-Peptides/blood
Animals

@article {pmid42786742,
year = {2026},
author = {Meng, J and Wang, Y and Wang, J and Chen, Y and Zhao, Z and Tang, Z and Cao, J and Zhang, X and Luo, H and Li, H and Wu, Y and Zhao, Y and Song, W and Zhang, YW},
title = {TMEM59 regulates microglial Aβ phagocytosis in a TREM2-dependent manner and acts as a potential therapeutic target for Aβ amyloidosis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71873},
doi = {10.1002/alz.71873},
pmid = {42786742},
issn = {1552-5279},
support = {82588301//National Natural Science Foundation of China/ ; U25A2072//National Natural Science Foundation of China/ ; 82501698//National Natural Science Foundation of China/ ; 82371420//National Natural Science Foundation of China/ ; 2025M782230//China Postdoctoral Science Foundation/ ; 2025B-07-39//Changping Laboratory/ ; },
mesh = {Animals ; *Microglia/metabolism ; *Membrane Glycoproteins/metabolism/genetics ; *Phagocytosis/physiology ; *Receptors, Immunologic/metabolism/genetics ; *Amyloid beta-Peptides/metabolism ; *Membrane Proteins/metabolism/genetics ; Mice ; *Alzheimer Disease/metabolism/genetics/pathology ; Mice, Transgenic ; *Amyloidosis/metabolism ; *Nerve Tissue Proteins/metabolism/genetics ; Disease Models, Animal ; Plaque, Amyloid/metabolism/pathology ; },
abstract = {INTRODUCTION: Microglia-mediated clearance of amyloid beta (Aβ) is crucial for mitigating Alzheimer's disease (AD) progression, yet the molecular regulators of microglial phagocytosis remain incompletely understood.

METHODS: We assessed AD-related phenotypes in 5xFAD mice with microglia-specific deletion of transmembrane protein 59 (TMEM59). Microglial transcriptomic profiling was performed using single-cell RNA sequencing (scRNA-seq). A chaperone-mediated autophagy-targeting chimera (CMATAC) peptide was developed to degrade TMEM59, and its therapeutic efficacy was evaluated.

RESULTS: Microglia-specific TMEM59 ablation attenuated cognitive deficits, Aβ plaque burden, and synapse loss in 5xFAD mice. TMEM59 deficiency reprogrammed disease-associated microglia toward a highly phagocytic state. Mechanistically, TMEM59 deficiency enhanced microglial Aβ phagocytosis in a triggering receptor expressed on myeloid cells 2 (TREM2)-dependent manner, as it stabilized TREM2 protein, whereas loss of TREM2 abolished these protective effects. Treatment with the TMEM59-degrading CMATAC peptide alleviated behavioral deficits and enhanced microglial Aβ phagocytosis in 5xFAD mice.

DISCUSSION: TMEM59 is a key regulator of microglial phagocytosis in AD and a novel target for amyloidosis intervention.},
}

Animals
*Microglia/metabolism
*Membrane Glycoproteins/metabolism/genetics
*Phagocytosis/physiology
*Receptors, Immunologic/metabolism/genetics
*Amyloid beta-Peptides/metabolism
*Membrane Proteins/metabolism/genetics
Mice
*Alzheimer Disease/metabolism/genetics/pathology
Mice, Transgenic
*Amyloidosis/metabolism
*Nerve Tissue Proteins/metabolism/genetics
Disease Models, Animal
Plaque, Amyloid/metabolism/pathology

@article {pmid42786847,
year = {2026},
author = {Yu, Y and Xu, Y and Xu, M},
title = {Therapeutic Strategies Targeting TREM2 for Alzheimer's Disease: Current Advances and Future Perspectives.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X509125260907101247},
pmid = {42786847},
issn = {1875-6190},
abstract = {BACKGROUND: Alzheimer's disease is a progressive neurodegenerative disorder characterized by cognitive decline and protein aggregation. The Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) has been identified as a key regulator of pathogenesis. This review summarizes current understanding of the receptor's structure, ligands, signaling, roles in disease, and therapeutic targeting strategies.

METHODS: A structured narrative review was conducted using targeted searches of PubMed, Web of Science, and Scopus, supplemented by citation tracking and searches of ClinicalTrials.gov.

RESULTS: TREM2 is a microglial immunoreceptor that recognizes apolipoprotein E and amyloid-β. Through the canonical DAP12-SYK axis, TREM2 regulates microglial phagocytosis, metabolism, and inflammatory responses. In Alzheimer's disease, it modulates amyloid-β clearance, tau hyperphosphorylation, and neuroinflammation in a stage-dependent manner. Loss-of-function variants increase disease risk. Therapeutic strategies include direct membrane-TREM2 agonistic antibodies, shedding-modifying antibody fragments, soluble TREM2-based approaches, gene-delivery platforms, small-molecule agonists, and indirect TREM2-associated natural-product modulators. These approaches differ in target-binding evidence, TREM2 dependence, disease-model relevance, safety, and clinical maturity.

DISCUSSION: TREM2 functions within a context-dependent framework in which gene dosage, disease stage, pathological substrate, microglial state, and activation duration jointly determine protective or maladaptive outcomes. Therapeutic modalities differ in specificity, brain exposure, reversibility, and translational readiness, while target engagement alone does not guarantee clinical benefit.

CONCLUSIONS: TREM2 remains a promising but context-sensitive therapeutic target. Successful translation will require controllable modulation, stage- and pathology-specific treatment windows, biomarkers of functional response, and patient stratification according to genotype, amyloid-β and tau burden, and microglial state.},
}

@article {pmid42787519,
year = {2026},
author = {Zaic, S and König, T and Keritam, O and Faber, V and Seifried, K and Silvaieh, S and Krajnc, N and Wurm, R and Parvizi, T and Macher, S and Rommer, P and Leutmezer, F and Bsteh, G and Stögmann, E and Berger, T and Zrzavy, T},
title = {Cerebrospinal fluid protein elevations in Alzheimer's disease are dissociated from immune cell composition.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70321},
pmid = {42787519},
issn = {2352-8737},
abstract = {INTRODUCTION: Elevated cerebrospinal fluid (CSF) inflammatory proteins have been reported in Alzheimer's disease (AD), yet whether they reflect peripheral immune cell infiltration or central nervous system (CNS)-intrinsic pathological processes remains unclear. We tested whether AD exhibits a distinct CSF protein signature and how it relates to CSF immune cell composition.

METHODS: We conducted a cross-sectional study of 64 participants: 22 with biomarker-confirmed AD (bioAD), 22 non-AD biomarker-negative cognitive controls (NAD-CC), and 20 other neurological disease controls (OND). CSF proteins were quantified using the Olink Target 96 Inflammation panel, and immune cell populations were characterized by multiparameter spectral flow cytometry. Cell-protein associations were assessed using hierarchical generalized linear models adjusted for age and sex.

RESULTS: BioAD showed widespread inflammatory and trophic protein elevation versus NAD-CC, with 21 proteins significantly increased (false discovery rate [FDR] q < 0.05), whereas NAD-CC was largely indistinguishable from OND. MMP-10 showed the largest effect (geometric mean ratio [GMR] = 2.10, 95% confidence interval [CI]: 1.53-2.88, p < 0.001). CSF immune cell populations did not differ significantly between groups; only discrete T-cell alterations were detected: reduced regulatory T cells in bioAD relative to NAD-CC (odds ratio [OR] = 0.69, 95% CI: 0.54-0.88, p = 0.023), but not relative to OND and minor memory subset shifts. CD8+ effector memory T cells and TNFSF14 showed the only detected AD-specific association: in bioAD, a 10-fold increase in CD8+ EM2 cells corresponded to 70% higher TNFSF14 (GMR = 1.70, 95% CI: 1.39-2.09, p < 0.0001).

DISCUSSION: In this feasibility-sized, cross-sectional cohort, CSF inflammatory proteins in AD appeared dissociated from immune-cell composition, potentially reflecting CNS-intrinsic processes and/or altered CSF barrier dynamics. The identified signature, including MMP-10, is hypothesis-generating and may complement conventional biomarkers for diagnosis and treatment monitoring, pending longitudinal validation.},
}

@article {pmid42787809,
year = {2026},
author = {Shimasaki, R and Kurihara, M and Sato, K and Bannai, T and Hatano, K and Ishii, K and Ihara, R and Ogawa, S and Iwata, A},
title = {Clinical utility of LUMIPULSE plasma p-tau217 to identify amyloid positivity among candidates for amyloid-targeting treatments in a real-world cohort.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70497},
pmid = {42787809},
issn = {2352-8729},
abstract = {INTRODUCTION: Increasing clinical use of amyloid-targeting treatments (ATTs) requires accessible biomarkers for Alzheimer's disease (AD). Although the utility of plasma phosphorylated tau 217 (p-tau217) is well established in research cohorts and its use for identifying amyloid positivity among ATT candidates is expanding into clinical practice, real-world evidence of its performance is lacking.

METHODS: We evaluated the utility of LUMIPULSE plasma p-tau217 in a real-world cohort of 99 patients screened for ATT eligibility.

RESULTS: Amyloid positivity was confirmed in 82 (82.8%) patients. Plasma p-tau217 predicted amyloid status, with an area under the curve of 0.93. With a cutpoint (0.1795 pg/mL) based on the Youden index, this approach achieved 95.1% sensitivity, 94.1% specificity, 98.7% positive predictive value, and 80.0% negative predictive value (NPV). Higher external thresholds led to a lower NPV, demonstrating that cut points must be optimized for clinical stages.

DISCUSSION: These findings provide real-world evidence supporting the clinical utility of p-tau217 for ATT candidates.},
}

@article {pmid42788819,
year = {2026},
author = {Busquets, MA and Sabaté, R and Álvarez-Berbel, I and Espargaró, A},
title = {Applications of Prussian blue nanoparticles in the treatment of neurodegenerative diseases.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/17435889.2026.2734070},
pmid = {42788819},
issn = {1748-6963},
abstract = {Neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, are characterized by progressive neuronal dysfunction associated with oxidative stress, chronic neuroinflammation, mitochondrial impairment, and pathological protein aggregation. Despite advances in symptomatic treatments, effective disease-modifying therapies remain limited. This review examines the emerging role of Prussian blue nanoparticles (PBNPs) as multifunctional nanoplatforms for neurodegenerative diseases and related neurological conditions, including ischemic stroke and nerve regeneration. Their intrinsic enzyme-mimetic (nanozyme) activities enable the catalytic scavenging of reactive oxygen and nitrogen species, mimicking key antioxidant enzymes such as superoxide dismutase and catalase. PBNPs may also modulate neuroinflammation, microglial activation, and the aggregation of neurotoxic proteins, including β-amyloid and α-synuclein. Advances in nanoparticle engineering to improve brain delivery, targeting, and pharmacokinetics are highlighted. Finally, the review critically addresses toxicological challenges, including biodistribution, organ accumulation, degradation, long-term persistence, and the potential effects of surface modifications, which remain key considerations for the safe clinical translation of PBNP-based therapeutic and theranostic strategies.},
}

@article {pmid42790169,
year = {2026},
author = {Zhang, B and Nan, J and Zhang, Y and Zhang, B and Ke, C and Wang, W and Wu, T and Xia, J and Yang, F and He, M and Tian, L and Yang, Z and Liang, C},
title = {Phytocannabinoid cannabidiol (CBD) in neurodegenerative diseases: From polypharmacology to drug development.},
journal = {European journal of medicinal chemistry},
volume = {320},
number = {},
pages = {119360},
doi = {10.1016/j.ejmech.2026.119360},
pmid = {42790169},
issn = {1768-3254},
abstract = {Cannabidiol (CBD) is a non-intoxicating phytocannabinoid that has attracted interest as a multi-target neurotherapeutic candidate for neurodegenerative diseases. CBD is a lipophilic terpenophenolic chemotype whose phenolic redox chemistry, membrane partitioning, cytochrome P450-mediated metabolism, and formulation-dependent exposure are central to its biological activity and translational limitations. In addition, CBD engages a broad target network relevant to neurodegeneration. Major components include cannabinoid receptors, transient receptor potential channels, peroxisome proliferator-activated receptor-γ, adenosine and serotonin signaling systems, voltage-gated calcium channels, and redox-regulatory pathways. These mechanisms converge on neuroinflammation, excitotoxicity, mitochondrial dysfunction, impaired proteostasis, and synaptic injury. Preclinical studies across models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis consistently support CBD's anti-inflammatory, antioxidant, mitochondria-protective, and neuroprotective pharmacology. The magnitude of these effects depends on dose, treatment timing, model system, and route of administration. Clinical evidence remains preliminary and is mainly symptomatic, with signals in agitation, sleep disturbance, spasticity, quality of life, and neuropsychiatric symptoms rather than proven disease modification. Key barriers to development include low and variable oral bioavailability, incomplete brain exposure data, uncertain active metabolite contributions, limited target-engagement biomarkers, and insufficient exposure-response definition. Future development of CBD and optimized cannabinoid-derived analogues will require medicinal chemistry strategies to improve potency, selectivity, metabolic stability, CNS exposure, and formulation performance. Parallel biomarker-driven clinical trials are needed to define pharmacokinetic-pharmacodynamic relationships and evaluate disease-modifying potential.},
}

@article {pmid42790767,
year = {2026},
author = {Bi, H and Sun, M and Ma, Q and Li, X and Wang, Y},
title = {RNA m6A demethylase FTO in central nervous system disorders: Mechanisms and therapeutic implications.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111942},
doi = {10.1016/j.pnpbp.2026.111942},
pmid = {42790767},
issn = {1878-4216},
abstract = {The fat mass and obesity-associated protein (FTO) is an obesity-related protein that is widely expressed in different tissues throughout the human body, with relatively high expression levels observed in the brain. Initial investigations into FTO mainly concentrated on its involvement in the development of obesity and diabetes. However, accumulating evidence has subsequently identified FTO as an N6-methyladenosine (m6A) demethylase, suggesting that it may participate in various neurological processes, including neural differentiation, synaptic plasticity, and neuroinflammation, through modulation of RNA m6A methylation. Increasing studies have demonstrated that FTO is involved in the pathophysiological mechanisms and therapeutic responses of a range of central nervous system (CNS) disorders, including Parkinson's disease, epilepsy, Alzheimer's disease, stroke, brain tumors, depression, autism, and substance use disorders. This review summarizes the potential roles of FTO in the pathogenesis and treatment of CNS disorders, with the aim of providing novel perspectives and potential therapeutic targets for further research and clinical intervention in CNS diseases.},
}

@article {pmid42791463,
year = {2026},
author = {Li, Z and Liu, Z and Zhang, Y and Lei, Y and Wang, Y},
title = {Brain-Wide Multi-Trait Genetic Integration Implicates Lysosomal and Metabolic Axes Linking Visual Disturbance and Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42791463},
issn = {1559-1182},
mesh = {*Alzheimer Disease/genetics/metabolism/complications ; Humans ; *Brain/metabolism/pathology ; Genome-Wide Association Study ; *Lysosomes/metabolism/genetics ; *Vision Disorders/genetics/metabolism/complications ; *Genetic Predisposition to Disease ; *Quantitative Trait, Heritable ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; },
abstract = {Visual impairment has been proposed as a potentially modifiable risk factor for dementia, including Alzheimer's disease (AD), but the biological mechanisms linking visual disturbance to AD remain unclear. It is unknown whether AD and visual disturbance share specific genetic determinants, how such effects are distributed across brain regions, and whether they converge on discrete molecular pathways that could be targeted for prevention or treatment. Multi-trait analysis of GWAS was applied to summary statistics from large-scale GWAS of AD and a visual disturbance (VD) phenotype, yielding VD-informed AD association statistics (VDAD). Gene-level associations were then mapped across brain tissues by integrating single-tissue and cross-tissue transcriptome-wide association studies, brain proteome-wide association analyses and gene-based tests. A small set of genes (GRN, PVR and RAB29) emerged as consistently associated with both AD and VDAD. A broader panel of genes showed partially overlapping but also phenotype-specific architectures, with PM20D1 and LRRC37A2 more prominent in AD and SLC41A1 and MTCH2 more strongly implicated in VDAD. These signals were anchored to frontal cortical, hippocampal, cerebellar and striatal tissues, suggesting involvement of circuits that integrate visual input with memory, motor control and balance. Network and pathway analyses highlighted a GRN-centered lysosomal axis and metabolic pathways linked to PM20D1 and SLC41A1 as candidate mechanisms bridging visual disturbance and AD risk. These findings support the view that visual disturbance-related AD risk is shaped by a limited set of genes and pathways that are supported across complementary molecular analyses and mapped to distributed brain/CNS reference tissues. These findings generate testable hypotheses for future studies with detailed visual phenotyping.},
}

*Alzheimer Disease/genetics/metabolism/complications
Humans
*Brain/metabolism/pathology
Genome-Wide Association Study
*Lysosomes/metabolism/genetics
*Vision Disorders/genetics/metabolism/complications
*Genetic Predisposition to Disease
*Quantitative Trait, Heritable
Phenotype
Polymorphism, Single Nucleotide/genetics

@article {pmid42791497,
year = {2026},
author = {Nevyhoštěná, M and Komersová, A and Svoboda, R and Pejchal, V and Pospíšilová, A and Muselík, J and Łapa, A and Koczurkiewicz-Adamczyk, P},
title = {Personalized 3D-Printed Affinisol-Based Pharmaceutical Delivery Systems: The Case Study for Alternative Sulfonamides for Alzheimer's Disease.},
journal = {Macromolecular bioscience},
volume = {26},
number = {9},
pages = {e70266},
doi = {10.1002/mabi.70266},
pmid = {42791497},
issn = {1616-5195},
support = {SGS_2026_006//Internal Grant Agency of the University of Pardubice/ ; },
mesh = {*Printing, Three-Dimensional ; *Alzheimer Disease/drug therapy/pathology ; Humans ; *Sulfonamides/chemistry/pharmacology/therapeutic use/pharmacokinetics ; Tablets ; Solubility ; *Precision Medicine ; *Drug Delivery Systems ; Drug Liberation ; },
abstract = {The use of hot melt extrusion combined with fused deposition modeling 3D printing was explored to enhance the solubility and bioavailability of poorly water-soluble compounds intended for Alzheimer's disease (AD) therapy. AD, a neurodegenerative disorder with no definitive treatment, affects millions worldwide, underscoring the urgent need for effective and personalized therapeutic strategies. Four sulfonamide-derived compounds, identified as potential AD therapeutics, were synthesized and successfully incorporated (loads between 10 and 50 wt.%) into customized, 3D-printed oral dosage forms. These 3D-printed tablets were evaluated for properties such as hardness, thermo-analytical characterization, dissolution, cytotoxicity, and stability. Notably, successful amorphization of the incorporated APIs was observed in most 3D-printed tablets, which may be critical for improving solubility. In vitro dissolution testing revealed multiple favorable release profiles, with several formulations demonstrating sustained or enhanced drug release suitable for the therapeutic requirements of AD. When compared to the dissolution data of the corresponding conventional matrix tablets, the present 3D-printed tablets offered superior or comparable dissolution characteristics, demonstrating the potential of personalized medicine and remote digital control for optimizing patient-specific treatments.},
}

*Printing, Three-Dimensional
*Alzheimer Disease/drug therapy/pathology
Humans
*Sulfonamides/chemistry/pharmacology/therapeutic use/pharmacokinetics
Tablets
Solubility
*Precision Medicine
*Drug Delivery Systems
Drug Liberation

@article {pmid42793309,
year = {2026},
author = {Narasimhappagari, J and Liu, L and Griffin, WST},
title = {Interleukin-1β-Induced Inflammatory Signaling and Myelin-Related Alterations in Oligodendroglia and Schwann Cells in Multiple Sclerosis: Modulatory Effects of Ibuprofen and Flurbiprofen.},
journal = {Current issues in molecular biology},
volume = {48},
number = {9},
pages = {},
doi = {10.3390/cimb48090953},
pmid = {42793309},
issn = {1467-3045},
support = {1R01AR084472-04/NH/NIH HHS/United States ; },
abstract = {Neuroinflammation, read as elevated levels of Interleukin-1β (IL-1β) and of its downstream signaling cascade, has been shown to play a neuropathogenic role in numerous neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Western blotting was used to determine the effects of IL-1β and its signaling cascade on Human Oligodendroglioma (HOG) and Schwann cells and to evaluate the potential therapeutic effects of Ibuprofen and Flurbiprofen on MS pathogenesis in vitro. IL-1β increased neuroinflammatory markers like TNFα, MyD88, βAPP, COX-2, and IL-6, as well as transcription factors like NFκB and STAT in HOG and Schwann cells, which in turn regulate the expression of other cytokines, resulting in the activation of the self-perpetuating Cytokine Cycle. The IL-1β treatment of HOG and Schwann cells decreased the levels of myelin Basic Protein (MBP) and synaptophysin while at the same time increasing βAPP. Autophagy markers like LAMP-2 and LC3B were downregulated. In contrast, treatment with Ibuprofen and Flurbiprofen effectively countered the harmful effects of IL-1β in MS. These in vitro studies show that IL-1β can play a possible detrimental role in facilitating neuropathogenesis, as seen in Alzheimer's and Parkinson's disease, and anti-inflammatory drugs Ibuprofen and Flurbiprofen have a potential role in modulating the neuroinflammation in MS.},
}

@article {pmid42793338,
year = {2026},
author = {Yang, Y and Kim, J and Kang, Y and Choi, S and Seo, J and Kim, S},
title = {Short-Term Cognitive and Behavioral Changes After Low-Intensity Transcranial Ultrasound Stimulation in Early Alzheimer's Disease: An IPTW-Adjusted Retrospective Exploratory Comparative Study.},
journal = {Brain sciences},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/brainsci16090913},
pmid = {42793338},
issn = {2076-3425},
support = {//Deepson Bio, Ltd/ ; },
abstract = {Background: Low-intensity ultrasound (LIUS) has been proposed as a non-invasive approach to modulate cerebrospinal fluid movement, glymphatic-lymphatic clearance, and amyloid-beta (Aβ) handling in Alzheimer's disease (AD). However, clinical comparisons in amyloid biomarker-confirmed patients receiving standard pharmacotherapy remain limited, and the short-term cognitive domains most likely to change after LIUS remain uncertain. Objective: The objective of this study was to compare 4-week changes in cognitive function, executive function, quality of life, and neuropsychiatric symptoms between amyloid PET-positive patients receiving add-on LIUS with donepezil-based standard treatment and those receiving donepezil-based standard treatment alone. Methods: This retrospective exploratory comparative cohort study included amyloid PET-positive patients with mild cognitive impairment or early AD who received donepezil-based standard treatment. The treatment cohort received 4 weeks of add-on LIUS at Dongtan or Bundang centers, whereas the comparator cohort received donepezil-based standard treatment alone at Soonchunhyang. Outcomes were changes from baseline to 4 weeks in Trail Making Test A (TMT-A), Trail Making Test B (TMT-B), Mini-Mental State Examination, Second Edition (MMSE-II), Quality of Life in Alzheimer's Disease (QoL-AD), and Neuropsychiatric Inventory (NPI). Group differences were examined using unadjusted change-score comparisons and stabilized inverse probability of treatment weighting (IPTW). Results: The full analysis set included 51 amyloid PET-positive participants receiving donepezil-based standard treatment: 20 who additionally received LIUS and 31 who received standard treatment alone. Compared with controls, the add-on LIUS group showed greater improvement in TMT-A completion time in unadjusted analysis (-20.0 ± 31.3 s vs. -0.1 ± 5.6 s; p = 0.011), and this association remained significant after IPTW adjustment. TMT-B showed a favorable but less robust pattern, with borderline findings in the primary Fail-excluded analyses and a significant result in the Fail = 300 sensitivity analysis. MMSE-II change did not differ between groups. NPI improved more in the add-on LIUS group in unadjusted analysis, although this finding was exploratory. Conclusions: In amyloid PET-positive patients receiving donepezil-based standard treatment, 4 weeks of add-on LIUS was associated with short-term improvement in TMT-A performance compared with standard treatment alone, while MMSE-II remained unchanged. The findings suggest a preliminary signal for processing-speed or visual-search improvement and support prospective randomized sham-controlled studies with harmonized cognitive testing and biomarker endpoints.},
}

@article {pmid42793674,
year = {2026},
author = {Pyrgelis, ES and Paraskevas, GP and Constantinides, VC and Boufidou, F and Stefanis, L and Kapaki, E},
title = {α-Synuclein Pathology in Idiopathic Normal Pressure Hydrocephalus: Evidence for Concomitant Synucleinopathy and Clinical Implications.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {18},
pages = {},
doi = {10.3390/diagnostics16182889},
pmid = {42793674},
issn = {2075-4418},
support = {Grant 2018 E01300001//General Secretariat of Research and Innovation/ ; },
abstract = {Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder characterized by gait impairment, cognitive decline, and urinary dysfunction. Despite improvements in diagnostic criteria and neuroimaging techniques, accurate diagnosis remains challenging due to clinical overlap with neurodegenerative diseases, particularly Alzheimer's disease (AD) and synucleinopathies. Biomarkers capable of improving differential diagnosis, patient selection for shunt surgery, and prognostic assessment are therefore of considerable clinical interest, as has been in AD biomarkers. This review summarizes current evidence regarding the role of α-synuclein as a potential additional marker in iNPH, focusing on its association with concomitant neurodegenerative pathology, clinical manifestations, and treatment outcomes. Available studies indicate that α-synuclein pathology may coexist with iNPH in a substantial proportion of patients, with reported positivity rates ranging from approximately 14% to 33%, depending on the detection method used. Patients with concomitant α-synuclein pathology may exhibit clinical features atypical for pure iNPH, including upper limb rigidity, olfactory dysfunction, hallucinations, autonomic dysfunction, sleep disturbances, and fluctuating cognitive impairment. However, current evidence does not support α-synuclein positivity as an independent predictor of poor response to cerebrospinal fluid (CSF) drainage or shunt surgery. On the contrary, α-synuclein presence may provide additional information regarding mixed neurodegenerative pathology and contribute to personalized clinical management. Future studies should focus on standardized detection techniques, larger multicenter cohorts, longitudinal follow-up, and integration of α-synuclein assessment with established AD biomarkers, neuroimaging findings, and clinical evaluation. Overall, α-synuclein represents a promising complementary marker in iNPH, with potential value in being taken into consideration during clinical evaluation and understanding disease heterogeneity.},
}

@article {pmid42794551,
year = {2026},
author = {Procopciuc, LM and Hangan, AC and Gog-Bogdan, S and Lucaciu, RL},
title = {The Tryptophan-Kynurenine Pathway as a Key Mediator of the Gut-Brain Axis in Depression and Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188122},
pmid = {42794551},
issn = {1422-0067},
mesh = {Humans ; *Kynurenine/metabolism ; *Tryptophan/metabolism ; *Alzheimer Disease/metabolism/microbiology ; *Depression/metabolism ; Animals ; Gastrointestinal Microbiome ; *Brain/metabolism ; *Brain-Gut Axis ; Signal Transduction ; },
abstract = {Depression and Alzheimer's disease are among the most prevalent and disabling disorders worldwide, imposing a substantial social, economic, and healthcare burden. Increasing evidence suggests that these conditions share several pathophysiological mechanisms, including chronic inflammation, oxidative stress, mitochondrial dysfunction, altered neurotransmission, and gut microbiota dysbiosis. In recent years, the microbiota-gut-brain axis has emerged as a key regulatory system linking gastrointestinal, immune, metabolic, and neural functions. Within this complex network, the tryptophan-kynurenine pathway has gained considerable attention as a critical mediator connecting gut microbial activity, immune responses, and central nervous system function. This review examines the role of the microbiota-gut-brain axis and the tryptophan-kynurenine pathway in the development and progression of depression and Alzheimer's disease. Particular emphasis is placed on the regulation of tryptophan metabolism by gut microbiota, the inflammatory activation of indoleamine 2,3-dioxygenase, and the generation of neuroactive kynurenine metabolites. Dysregulation of these processes may reduce serotonin synthesis while promoting the accumulation of neurotoxic compounds such as quinolinic acid and 3-hydroxykynurenine, thereby contributing to neuroinflammation, excitotoxicity, cognitive decline, and depressive symptoms. Current evidence also highlights the therapeutic potential of interventions targeting gut microbiota composition and kynurenine pathway activity. A better understanding of these interconnected mechanisms may facilitate the identification of novel biomarkers and the development of personalized strategies for the prevention and treatment of both psychiatric and neurodegenerative disorders.},
}

Humans
*Kynurenine/metabolism
*Tryptophan/metabolism
*Alzheimer Disease/metabolism/microbiology
*Depression/metabolism
Animals
Gastrointestinal Microbiome
*Brain/metabolism
*Brain-Gut Axis
Signal Transduction

@article {pmid42794584,
year = {2026},
author = {Paul, PS and Borenstein-Katz, A and Shmeit, K and Wille, H and Kar, S},
title = {Attenuation of Tau-Mediated β-Amyloid1-42 Aggregation by Native PLGA Nanoparticles and Its Relevance to Alzheimer Disease Pathology.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188152},
pmid = {42794584},
issn = {1422-0067},
support = {RES0035124//Alzheimer Society of Canada and Northwest Territories/ ; MOP-84480/CAPMC/CIHR/Canada ; },
mesh = {*Amyloid beta-Peptides/metabolism/chemistry ; *tau Proteins/metabolism/chemistry ; *Alzheimer Disease/metabolism/pathology ; *Nanoparticles/chemistry ; *Peptide Fragments/metabolism/chemistry ; *Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Humans ; Protein Aggregates/drug effects ; Animals ; *Protein Aggregation, Pathological/metabolism ; },
abstract = {Alzheimer's disease (AD) is an unremitting neurodegenerative disorder characterized by the presence of extracellular β-amyloid (Aβ)-containing neuritic plaques, intracellular tau-positive neurofibrillary tangles and loss of selected neurons in the brain. Evidence suggests that aggregation of Aβ and tau via synergistic interactions initiates a cascade of events, leading to development of AD pathology. Thus, many studies are being pursued to develop small molecules/drugs that can target both Aβ and tau as an effective AD treatment strategy. In this study, we evaluated effects of native PLGA nanoparticles on tau-mediated Aβ1-42 aggregation using biophysical, structural, spectroscopic and biochemical approaches. Our results show that 0N4R tau seeds enhanced Aβ1-42 aggregation, and that this effect is mitigated by native PLGA. Additionally, PLGA inhibited Aβ1-42 aggregation induced by both 0N4R and 2N4R tau isoforms. The presence of PLGA during the formation of tau seeds or pretreatment of tau seeds with PLGA attenuates subsequent Aβ1-42 aggregation. Interestingly, monomeric 0N4R tau, unlike 0N4R tau seeds, suppressed Aβ1-42 aggregation, which is diminished further by PLGA nanoparticles. However, we have not addressed the implications of native PLGA on tau/Aβ1-42 interaction using any cellular or animal models of AD. Nevertheless, our results reveal that tau seeds and monomeric tau can differentially influence Aβ1-42 aggregation, which is mitigated by native PLGA under in vitro conditions, providing a rationale to study it further under an in vivo paradigm to examine its significance in AD pathogenesis.},
}

*Amyloid beta-Peptides/metabolism/chemistry
*tau Proteins/metabolism/chemistry
*Alzheimer Disease/metabolism/pathology
*Nanoparticles/chemistry
*Peptide Fragments/metabolism/chemistry
*Polylactic Acid-Polyglycolic Acid Copolymer/chemistry
Humans
Protein Aggregates/drug effects
Animals
*Protein Aggregation, Pathological/metabolism

@article {pmid42794615,
year = {2026},
author = {Hedström, AK},
title = {Interpreting Viral Associations in Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188185},
pmid = {42794615},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/virology ; Animals ; *Virus Diseases/complications/virology ; Parkinson Disease/virology ; Amyotrophic Lateral Sclerosis/virology ; Herpesvirus 4, Human ; },
abstract = {Viral infections have been associated with multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), but the associations may reflect different relationships to the disease process. This review evaluates evidence for viral involvement in disease initiation, modification of established disease, impaired viral control secondary to disease or treatment, and incidental detection. The strongest temporal evidence concerns Epstein-Barr virus (EBV) and MS. Prospective data place EBV seroconversion before clinical onset and the first observed increase in serum neurofilament light chain, while mechanistic studies link EBV infection, B-cell biology, and CNS-directed immunity. However, evidence that ongoing EBV activity modifies established MS remains limited. In AD, experimental studies support interactions between herpesviruses and AD-associated proteins, while the reduced incidence of all-cause dementia after herpes zoster vaccination suggests that viral or immunological pathways may be modifiable, without establishing that a specific herpesvirus initiates AD. Viral associations in PD rely mainly on epidemiological, experimental, and postmortem findings. Human pegivirus detection in a subset of PD brains remains a candidate association requiring independent confirmation and evidence of biological activity. Evidence in ALS is similarly limited. Enterovirus detection has been inconsistent, and altered human endogenous retrovirus K (HERV-K) expression in postmortem tissue does not establish an acquired viral infection. Stronger inference across these diseases will require longitudinal studies relating viral activity and antiviral immunity to subsequent disease-related changes, together with intervention studies that document the intended effect on the implicated viral process and separately assess subsequent disease risk or progression.},
}

Humans
*Neurodegenerative Diseases/virology
Animals
*Virus Diseases/complications/virology
Parkinson Disease/virology
Amyotrophic Lateral Sclerosis/virology
Herpesvirus 4, Human

@article {pmid42778072,
year = {2026},
author = {Li, Y and Xue, X and Luo, H and Chen, D and Yang, S and Huang, X and Li, Y},
title = {Investigating the therapeutic mechanism of leech in vascular dementia: An integrated approach combining network pharmacology and experimental validation.},
journal = {Brain research bulletin},
volume = {245},
number = {},
pages = {112131},
doi = {10.1016/j.brainresbull.2026.112131},
pmid = {42778072},
issn = {1873-2747},
abstract = {BACKGROUND: Vascular dementia (VaD), the second leading cause of dementia following Alzheimer's disease, results from the reduction in cerebral blood flow. Medicinal leeches (SZ) in traditional Chinese medicine (TCM), a classic remedy for promoting blood circulation and improving blood stasis, have shown capabilities to relieve neuroinflammation and repair the blood-brain barrier (BBB) integrity. However, the efficacy and the underlying mechanisms of medicinal leeches in treating VaD remain unclear.

OBJECTIVE: This study aimed to explore the efficacy of medicinal leeches in treating VaD and its molecular mechanisms.

METHODS: An in vivo VaD model of rats was created via a two-vessel occlusion (2VO) ischemia protocol. Learning and memory functions in rats were assessed via the water maze test, Y-maze test, and novel object recognition test. The neuronal injury in rat hippocampus was assessed by H&E and Nissl staining. Network pharmacology (NP) and molecular docking depicted a "SZ-Compounds-Targets" network and visualized the binding pattern between core components of medicinal leeches and key targets of VaD, respectively. Transmission electron microscopy (TEM), ELISA, quantitative PCR, and Western blotting were performed to validate the involvement of the TLR4/NF-κB signaling pathway in leech treatment against VaD.

RESULTS: Medicinal leeches alleviated the cognitive deficits and neuronal injuries in VaD rats. Seven key targets were predicted as the leading contributors to the neuroprotective potential of medicinal leeches against VaD. Enrichment analyses further showed that the Toll-like receptor and NF-κB signaling pathways were enriched in the key targets of medicinal leeches. Experimental assays showed that expression levels of TLR4, MyD88, p-p65, and pro-inflammatory mediators were significantly elevated in VaD rats, which were further enhanced by LPS induction. Encouragingly, leech treatment significantly downregulated their levels.

CONCLUSION: Medicinal leeches can effectively alleviate the learning and cognitive impairments, neurological pathology in the hippocampal CA1 region, and the loss of BBB integrity in VaD rats. Moreover, medicinal leeches can suppress the neuroinflammation in VaD rats through inhibiting the TLR4/NF-κB signaling pathway.},
}

@article {pmid42778217,
year = {2026},
author = {Shinagawa, S and Nagata, T},
title = {Patient-Specific Clinical Formulation for Agitation in Alzheimer's Disease: Beyond Group-Level Evidence.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {6},
pages = {e70220},
doi = {10.1111/psyg.70220},
pmid = {42778217},
issn = {1479-8301},
support = {24K10690//JSPS KAKENHI/ ; },
mesh = {Humans ; *Alzheimer Disease/complications/psychology/therapy ; *Psychomotor Agitation/therapy/etiology/drug therapy/psychology ; Japan ; *Antipsychotic Agents/therapeutic use ; },
abstract = {Agitation in Alzheimer's disease (AD) is clinically heterogeneous. Patients who meet the same syndromic definition can differ in the behaviour of greatest concern, the factors that precipitate or sustain it, the risks involved and their response to treatment. Randomised trials are essential for estimating average treatment effects; individual treatment selection also requires patient-specific clinical information. This review considers patient-specific clinical formulation as a practical way to connect group-level evidence with individual treatment decisions. The formulation makes explicit what is being treated, which contributors are plausible, which contextual or reversible factors matter, what outcome would count as meaningful improvement and when treatment should be changed or stopped. Treatment response then becomes additional clinical information: early benefit, adverse effects or an unexpected course may support or call into question the initial formulation. Non-pharmacological care and treatment of reversible causes remain the foundation of management, with medication reserved for agitation that is severe, persistent, dangerous or highly distressing. For Japan, we propose a formulation summary as a prototype for shared documentation across care settings; its feasibility and clinical value require prospective evaluation. Moving beyond group averages entails applying evidence more carefully to the needs of the individual patient.},
}

Humans
*Alzheimer Disease/complications/psychology/therapy
*Psychomotor Agitation/therapy/etiology/drug therapy/psychology
Japan
*Antipsychotic Agents/therapeutic use

@article {pmid42778344,
year = {2026},
author = {Tao, L and Liu, N and Zhang, W and Yang, Z and Xing, W and Wu, L and Hou, L and Wei, P and Xie, Y and Han, W and Liu, Y and Jin, Y and Xiang, L and Liu, X and Ma, W and Hu, P and Li, W and Zhou, W and Wang, S and Chen, H and Liu, P and Yin, D and Li, Y and Dooley, S and Zhang, L and Xu, J and Ji, G and Liu, C},
title = {Butyrylcholinesterase alleviates hepatic stellate cell activation via paracrine muscarinic signalling.},
journal = {Gut},
volume = {},
number = {},
pages = {},
doi = {10.1136/gutjnl-2026-338932},
pmid = {42778344},
issn = {1468-3288},
abstract = {BACKGROUND: Butyrylcholinesterase (BuChE) is a metabolic enzyme implicated in Alzheimer's disease, detoxification and depression. Although reduced BuChE expression is recognised in cirrhosis, its functional role in fibrogenesis remains undefined.

OBJECTIVE: We investigated whether BuChE regulates fibrosis by modulating acetylcholine (ACh) bioavailability and identified downstream cholinergic signalling.

DESIGN: BuChE expression was assessed via qPCR and immunostaining in patient biopsies. Its contribution was studied using Buche [ΔHep], Buche [KI/KI-Hep] mice, pharmacological inhibition, mutant BuChE conditioned medium and recombinant protein. ACh release and muscarinic ACh receptor (ChRM) function were measured using patch-clamp and calcium mobilisation assay; ChRM3 role was tested via Chrm3 [ΔHSC] mice and AAV6-mediated overexpression.

RESULTS: BUCHE mRNA and serum activity are significantly downregulated in fibrotic patients and mice, correlating negatively with F stage and alpha-smooth muscle actin expression. BuChE is predominantly expressed in hepatocytes in the liver, which can be reduced by transforming growth factor beta or platelet-derived growth factor treatment, and its anti-fibrotic function requires enzymatic activity. Hepatocyte BuChE deletion or inhibition increases hepatic stellate cell (HSC) activation and fibrosis across multiple models, whereas overexpression is protective, establishing causality. Loss of BuChE leads to accumulation of unmetabolised ACh, which activates HSCs as a damage associated molecular pattern signal via ChRM3-NF-κB signalling. Chrm3 [ΔHSC] mice exhibit attenuated HSC activation and fibrosis, whereas Chrm3 overexpression promotes fibrogenesis.

CONCLUSION: Hepatocyte injury disrupts BuChE activity, causing local ACh accumulation and subsequent HSC activation via ChRM3 signalling. This newly identified cholinergic circuit drives fibrosis and represents a druggable target for therapeutic intervention.},
}

@article {pmid42779999,
year = {2026},
author = {Kaser, AN and Stricker, JL and Hughes, MA and Corriveau-Lecavalier, N and Boots, EA and Machulda, MM and Fields, JA and Jones, DT and McCarter, SJ and Botha, H and Coburn, RP and Bermudez, C and Neth, BJ and Graff-Radford, J and Ramanan, VK and Stricker, NH},
title = {Feasibility of remote self-administered cognitive assessment in an Alzheimer's disease treatment clinic.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.15.26362283},
pmid = {42779999},
abstract = {INTRODUCTION: Remote cognitive assessments offer an accessible, scalable way to support clinical characterization and longitudinal monitoring of cognition. This study evaluates the feasibility of implementing Mayo Test Drive (MTD), a remote, self-administered digital cognitive assessment, within a specialized clinic focused on eligibility assessments for anti-amyloid therapies for Alzheimer's disease (AD).

METHOD: Two-hundred and nine (N =209) patients (M age =71.2, 53% female) were evaluated through the Mayo Clinic Rochester Alzheimer's Disease Treatment Clinic (ADTC) and had the opportunity to complete MTD, either as a remote, patient-initiated session through a patient-facing healthcare portal or during an in-clinic neuropsychological evaluation.

RESULTS: Clinical diagnoses included 55.2% mild cognitive impairment (MCI), 31.0% mild dementia, and 11.6% moderate dementia, in addition to 2.2% cognitively unimpaired (CU), as determined by neurology consensus at a multidisciplinary case conference. Among those who initiated MTD (n =197/209), 97.5% completed a session (70.6% remotely, 26.9% in clinic). Completion rates were high across diagnostic groups and did not significantly differ by clinical severity (p =.12): CU (100%), MCI (99.1%), mild dementia (97.0%), and moderate dementia (89.5%). Remote completion rates overall were high (97.9%). Among completers, administration setting (remote vs. in-clinic) did not significantly differ by clinical stage, χ²(3)=2.37, p =.49. Reasons for non-initiation included not receiving or opening portal messages and other/unknown factors.

DISCUSSION: Remote digital cognitive assessment is feasible within the context of clinic eligibility evaluations for AD therapies. The high completion rates of MTD across clinical impairment levels in this setting support development of paths for broader use in cognitive characterization in AD care.},
}

@article {pmid42780868,
year = {2026},
author = {Johnson, JC and Kashyap, B and Gustafson, SK and O'Brien, M and Frey, WH and Svitak, AL and Hanson, LR},
title = {Safety and tolerability of intranasal insulin in Parkinson's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1875165},
pmid = {42780868},
issn = {1664-2295},
mesh = {Humans ; Administration, Intranasal ; Female ; Male ; Aged ; *Insulin/administration & dosage/adverse effects ; *Parkinson Disease/drug therapy ; Double-Blind Method ; Middle Aged ; Aged, 80 and over ; *Hypoglycemic Agents/administration & dosage/adverse effects ; Adult ; },
abstract = {BACKGROUND: Repurposing therapeutic treatments for diabetes may be a promising strategy for the treatment of neurodegenerative disorders. Intranasal insulin (INI) is shown to improve memory, attention, and cognition in Alzheimer's dementia. Associations between the etiology of Parkinson's Disease (PD), brain glucose hypometabolism, and central insulin resistance suggest INI as a promising treatment for PD.

METHODS: A phase II single center, randomized, double-blind clinical trial was conducted in 30 participants with PD, aged 41-89, MoCA ≥ 16, on a stable dose of anti-PD medications. Participants were randomized to receive intranasal treatment for 21 days with either placebo, or 20, 40, or 80 IU of regular insulin (INI) using SipNose intranasal device. Primary outcomes of safety and tolerability were assessed in 30 participants by monitoring hypoglycemia, weight, and adverse events. Cognitive, mood, and motor measures were collected pre- and post-treatment for secondary outcome analysis and assessed in 28 participants.

RESULTS: No significant changes in weight or serum insulin were observed during the study. No hypoglycemic values (<70 mg/dL) were recorded 15 or 30 min post-IN dose. Nasal irritation and nosebleeds were the most common adverse events, with most categorized as "mild." Several secondary outcomes (e.g., verbal fluency and recall) improved from baseline in the 40 IU/INI arm only, though not significantly more than in the placebo arm. No other outcomes assessed (mood, apathy, motor) improved under INI treatment.

CONCLUSION: INI exhibits an acceptable safety profile in patients with PD. Further studies to investigate if INI has a positive impact on cognitive and motor symptoms in PD are warranted.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04251585 Identifier, NCT04251585.},
}

Humans
Administration, Intranasal
Female
Male
Aged
*Insulin/administration & dosage/adverse effects
*Parkinson Disease/drug therapy
Double-Blind Method
Middle Aged
Aged, 80 and over
*Hypoglycemic Agents/administration & dosage/adverse effects
Adult

@article {pmid42782577,
year = {2026},
author = {Salardini, A and Azarbar, S},
title = {Cognition in Cardiovascular Disease.},
journal = {Current neurology and neuroscience reports},
volume = {26},
number = {1},
pages = {},
pmid = {42782577},
issn = {1534-6293},
mesh = {Humans ; *Cardiovascular Diseases/complications/pathology/psychology ; *Cognition Disorders/etiology ; *Cognition/physiology ; Brain/pathology ; Animals ; },
abstract = {PURPOSE OF REVIEW: Acute cerebrovascular events once dominated efforts to protect the brain from cardiovascular disease. As stroke prevention and treatment have advanced, attention has broadened to the more continuous vascular processes that contribute to cognitive decline across later life. This review organizes cardiovascular brain injury by route, direct structural injury versus indirect mediated pathways, and tempo, acute events versus chronic processes, with vessel caliber determining lesion topography.

RECENT FINDINGS: Vascular and Alzheimer pathology commonly coexist in older adults with cognitive impairment, and their relationship appears bidirectional but asymmetric: Alzheimer pathology can directly injure the cerebral vasculature, while vascular dysfunction may facilitate Alzheimer pathology and, more clearly, accumulated vascular injury lowers the threshold at which Alzheimer pathology becomes clinically expressed. Covert infarction, microbleeds, white matter disease, and blood-brain barrier disruption accumulate into a cumulative vascular substrate that erodes cognition over decades without requiring a recognized clinical event, and the clinical syndrome follows the lesion, with the subcortical dysexecutive phenotype the modal presentation. Evidence from SPRINT MIND, FINGER, US POINTER, BRAIN-AF, LACI-2, CREST-2, and Mendelian randomization identifies blood pressure control as the best-established intervention, uses discordant and null findings to refine presumed mechanisms, and frames the emerging dilemma of anti-amyloid therapy in patients with substantial vascular disease. In the mixed vascular and Alzheimer disease that dominates late-life dementia, the vascular component is often the more modifiable, and cardiovascular risk management remains among the most actionable strategies for preserving cognition.},
}

Humans
*Cardiovascular Diseases/complications/pathology/psychology
*Cognition Disorders/etiology
*Cognition/physiology
Brain/pathology
Animals

@article {pmid42783767,
year = {2026},
author = {Kang, Z and Meng, R and Nie, M and Wang, T},
title = {Gut Microbial Metabolism as a Dynamic Interface in Neurodegenerative Diseases.},
journal = {Metabolites},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/metabo16090642},
pmid = {42783767},
issn = {2218-1989},
support = {No.82405557//China National Natural Science Foundation of youth project/ ; KM202410025018//R&D Program of Beijing Municipal Education Commission 2024: Study on the improvement of clinical symptoms and mechanism of acupuncture in amyotrophic lateral sclerosis/ ; 20250639//Young Elite Scientists Sponsorship Program of the Beijing High Innovation Plan/ ; 2024-QNRC2-B08//2024-2026 Chinese Association of Chinese Medicine young Talent lifting project/ ; },
abstract = {Gut microbial metabolism links intestinal ecology with systemic physiology and neural pathology, but its effects vary across disease stage, tissue compartment, and host background. This review uses Alzheimer's disease (AD) as the principal model and compares selected features with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Across the AD continuum, fermentation-related changes appear in prodromal cohorts, whereas broader alterations in amino acid products, host-microbial co-metabolites, bile acids, and lipids accompany mild cognitive impairment and dementia. These group-level patterns do not constitute a fixed patient trajectory. Microbial production, intestinal absorption, hepatic conversion, renal clearance, barrier integrity, and tissue-specific receptors jointly determine biological exposure. Experimental studies connect short-chain fatty acids and indole derivatives with epithelial and neuroimmune homeostasis, while imidazole propionate, trimethylamine N-oxide, selected kynurenine products, and remodeled bile acid pools engage vascular, inflammatory, amyloid, or tau-related pathways. Cerebral pathology can also remodel the intestinal ecosystem, creating reciprocal feedback. Apolipoprotein E4 modifies lipid handling, vascular permeability, and immune responses, helping to explain why comparable metabolic profiles may carry different consequences among individuals. Translation therefore requires more than a change in community composition. Trials must verify microbial function, metabolite target engagement, AD biomarker response, and clinical benefit in appropriately stratified participants. Shared pathways in PD and ALS provide comparison points, but disease-specific cells, proteinopathies, and treatment exposures constrain direct transfer of AD-derived targets.},
}

@article {pmid42769555,
year = {2026},
author = {Huang, L and Cheng, P and Liu, G and Xiang, Y and Hong, Z and Le, W},
title = {Myelin Impairment and Regeneration in the Central Nervous System: Molecular Mechanisms, Diseases, and Prospective Therapeutic Targets.},
journal = {MedComm},
volume = {7},
number = {10},
pages = {e71017},
pmid = {42769555},
issn = {2688-2663},
abstract = {Myelin plasticity is fundamental to the formation of neural networks and the optimization of neural functions, shaping circuits governing emotion, cognition, sensation, and motor control. Synthesized by oligodendrocytes, myelin undergoes lifelong remodeling that demands high metabolic activity; this renders the myelin-oligodendrocyte unit highly susceptible to metabolic stress, aging, and pathological insults. While demyelination is the core hallmark of various chronic neurological disorders, this review specifically highlights its emerging role in Alzheimer's disease (AD). Myelin impairment is increasingly recognized as an early pathological event in AD, potentially preceding the classic accumulation of amyloid plaques and neurofibrillary tangles. Here, we provide a comprehensive overview of myelin structure and function, evaluating the potential of tracking myelin changes as early diagnostic biomarker for AD. We further synthesize recent evidence regarding myelin pathology across a spectrum of central nervous system disorders including multiple sclerosis, leukodystrophies, cerebral small vessel disease, psychiatric disorders, and traumatic injury, highlighting the underlying pathological mechanisms. Furthermore, we examine emerging therapeutic strategies, ranging from pharmacological interventions to noninvasive stimulation, aimed at restoring oligodendroglial function and promoting remyelination. Finally, we offer a forward-looking perspective on myelin regeneration research, emphasizing its critical potential as a novel therapeutic target for AD and other neurodegenerative conditions.},
}

@article {pmid42769797,
year = {2026},
author = {Patel, MM and Nguyen, MD and Pistone, ES and Chowdhury, A and Phan, MH and El Ayadi, A and Song, J and Erickson, M},
title = {Out of the Fire, Into the Fog: Association Between Early Mechanical Ventilation and Delirium in Hospitalized Burn Patients.},
journal = {Cureus},
volume = {18},
number = {8},
pages = {e114981},
pmid = {42769797},
issn = {2168-8184},
abstract = {Introduction Delirium is a common and clinically significant complication among hospitalized burn patients, associated with increased morbidity, mortality, and healthcare utilization. While multiple factors contribute to delirium risk, mechanical ventilation has been associated with delirium, although this relationship may reflect underlying illness severity and ICU-level treatment exposure. However, large-scale, multicenter administrative analyses comparing coded outcomes between mechanically ventilated and non-ventilated burn patients remain limited. Methods A retrospective cohort study was conducted using the TriNetX (TriNetX, LLC, Cambridge, Massachusetts, United States) database to identify adult hospitalized burn patients with International Classification of Diseases (ICD)-coded burns involving ≥20% total body surface area. Patients were stratified into two cohorts based on receipt of mechanical ventilation within five days of the index burn event. Exclusion criteria included age <18 years and diagnoses of dementia, Alzheimer's disease, substance use disorders, or other conditions associated with baseline cognitive impairment. Cohorts were propensity score matched for age, sex, race, ethnicity, ICD-coded burn extent history, hypertension, diabetes, ischemic heart disease, sepsis, inhalation injury, and respiratory disorders. Outcomes assessed within 30 days included administratively documented delirium, disorientation, mortality, anxiety disorders, depressive disorders, and acute stress-related disorders. Results There were 1,541 patients in each cohort after matching. Ventilated patients had higher rates of administratively documented delirium (risk ratio (RR): 2.16, 95% CI: 1.51-3.09, p<0.0001), mortality (RR: 5.06, 95% CI: 4.23-6.05, p<0.0001), anxiety disorders (RR: 1.88, 95% CI: 1.58-2.21, p<0.0001), disorientation (RR: 3.39, 95% CI: 2.27-5.06, p<0.0001), and acute stress-related disorders (RR: 1.77, 95% CI: 1.40-2.22, p<0.0001). Depressive disorders were not significantly different between cohorts (RR: 1.42, 95% CI: 0.85-2.39, p=0.19). Discussion Early mechanical ventilation was associated with higher rates of administratively documented delirium, mortality, anxiety disorders, disorientation, and acute stress-related disorders among adult hospitalized burn patients. However, these findings likely reflect both ICU-level treatment exposure and substantial residual confounding by underlying illness severity. Early mechanical ventilation may identify a high-risk subgroup that warrants structured neurocognitive monitoring, psychological screening, sedation-conscious care, and post-extubation support. Given the observational design and reliance on administrative coding, these findings should be interpreted as hypothesis-generating.},
}

@article {pmid42769842,
year = {2026},
author = {Hou, C and Gao, Y and Wang, H},
title = {Exercise timing as a potential temporal regulator of neurolymphatic physiology in neurodegenerative proteinopathies: a mechanistic framework.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1879617},
pmid = {42769842},
issn = {1662-4548},
abstract = {Although physical activity is consistently associated with lower risks of cognitive decline, dementia, and Parkinson's disease, most exercise research in neurodegeneration still defines exposure by dose-based variables such as duration, intensity, frequency, step count, and cardiorespiratory fitness. This framework is useful for public-health guidance but biologically incomplete for progressive proteinopathies, in which the temporal accumulation and dissemination of misfolded proteins are central to disease evolution. In this review, we propose a temporal intervention framework in which exercise timing is treated as a mechanistic variable that may influence neurodegenerative biology through glymphatic-meningeal lymphatic clearance, vascular pulsatility, circadian alignment, and sleep architecture. We focus on Alzheimer's disease and Parkinson's disease because tau and α-synuclein propagation are disease-relevant processes that may be most amenable to intervention during preclinical or prodromal stages. Morning exercise may act primarily through circadian entrainment, afternoon exercise through vascular-metabolic stimulation, appropriately timed evening or low-intensity activity through sleep-related pathways, and sedentary fragmentation through effects on daytime cerebrovascular dynamics and rest-activity rhythm stability. Although the glymphatic-meningeal lymphatic axis provides a plausible link between timed exercise and extracellular protein handling, current human evidence remains indirect and relies heavily on imaging surrogate markers. Future matched-dose trials should integrate accelerometry, sleep physiology, circadian measures, vascular assessments, neurolymphatic imaging, and disease-specific protein biomarkers, including tau PET, plasma p-tau217, and α-synuclein seed amplification assays. Timed exercise should therefore be viewed as a testable biological perturbation that may clarify whether movement timing influences protein propagation in early neurodegenerative disease, not as a proven disease-modifying treatment.},
}

@article {pmid42770363,
year = {2026},
author = {Chi, L and Xu, F and Dai, X and Li, Z and Li, J and Li, Z},
title = {Immunity and Inflammation in Alzheimer's Disease: A Narrative Review on Mechanisms and Therapeutic Prospects.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050493089260903062914},
pmid = {42770363},
issn = {1875-5828},
abstract = {Alzheimer's Disease (AD) is an age-related neurodegenerative disorder of the Central Nervous System (CNS), characterized by amyloid-β (Aβ) deposition and Neurofibrillary Tangles (NFTs) caused by the hyperphosphorylation of tau protein. Neuroinflammation is an increasingly recognized feature of AD, playing a critical role in disrupting the immune microenvironment within the brain parenchyma. High levels of various inflammatory mediators have been documented in both AD patients and experimental AD models. Similarly, multiple immune cells have been found to accumulate in the brain parenchyma, the meninges, and the choroid plexus. Therefore, antiinflammatory therapies, including Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and immune regulatory strategies hold promise as potential novel approaches for the prevention and treatment of AD. Currently, a variety of anti-inflammatory agents and immunotherapies have demonstrated efficacy in AD animal models, and several clinical trials of immunotherapeutic interventions have been completed or are underway. This review systematically summarizes the core pathophysiological mechanisms by which inflammatory and immune dysfunctions contribute to AD pathogenesis and explores potential therapeutic interventions targeting these mechanisms, thereby providing theoretical insights for clinical translational research on AD treatment.},
}

@article {pmid42770364,
year = {2026},
author = {Pluta, R and Ułamek-Kozioł, M},
title = {Vitamin C versus Alzheimer's Disease. Commentary on the Effect of Ascorbic Acid on the Transgenic Drosophila Expressing Human Aβ-42 in the Neurons.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050513704260903053055},
pmid = {42770364},
issn = {1875-5828},
abstract = {A recent article by Siddique et al. published in Current Alzheimer's Research suggests that vitamin C may have a neuroprotective effect in Alzheimer's disease, which inspired us to write this commentary. In this commentary, we focus on the effects of vitamin C treatment on amyloid in a transgenic Drosophila melanogaster model of Alzheimer's disease. It should be noted that some of the information presented in this article raises more questions than it answers. The article does not provide a clear answer to the question posed in the title. We note that the authors demonstrated, to a very limited extent, the ameliorative effects of vitamin C on oxidative stress, cholinergic function, improved behavior, and prolonged lifespan, yet their enthusiasm for the therapeutic potential of vitamin C in Alzheimer's disease has not faded. In conclusion, the work contains controversial and speculative statements; therefore, drawing far-reaching conclusions and applying vitamin C to Alzheimer's disease are not justified by the available evidence.},
}

@article {pmid42770365,
year = {2026},
author = {Mehra, A and Sharma, R and Mittal, A},
title = {Cholinesterase Inhibitors in Alzheimer's Disease: Medicinal Chemistry, Mechanistic Insights, and Emerging Multitarget Strategies.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273435274260907101735},
pmid = {42770365},
issn = {1996-3181},
abstract = {Alzheimer's disease (AD) is the leading neurodegenerative disorder in the world. Although several decades of research have focused on its multifactorial pathogenesis, treating it remains a great challenge. The approved treatment options include cholinesterase inhibitors (ChEIs), which are the most common symptomatic treatment choice. These drugs act by inhibiting acetylcholinesterase (AChE) and, in some cases, butyrylcholinesterase (BuChE), preventing the breakdown of acetylcholine and increasing cholinergic neurotransmission in the brain. This review provides a broad consideration of ChEIs, focusing on their bioactivity, biochemical action, clinical significance, and SAR trends. It provides a comparative analysis of all the major chemical classes of ChEIs, namely the carbamates and organophosphates, as well as multiple heterocyclic scaffolds, with particular assessment of BBB permeability, metabolic stability, and toxicity attributes. Recent advances in medicinal chemistry have led to a shift in interest toward multi-target-directed ligands (MTDLs) that are designed not only to inhibit ChEs but also to exert antioxidant, anti-inflammatory, anti-amyloid, and metalchelating activity. These can target multiple pathogenic mechanisms to achieve a better therapeutic effect and neuroprotection. This review is based on a robust literature search conducted between 2020 and 2025. The progress, limitations, and prospects of ChEIs in the treatment of AD are critically assessed in this work. It also underscores the need for rational drug design to develop multitargetdirected drugs that may have disease-modifying effects, to overcome the limitations of existing symptomatic cholinesterase-inhibitor monotherapy.},
}

@article {pmid42771693,
year = {2026},
author = {Tariot, PN and Citrome, L and Clevenger, CK and Jackson, WC and Montano, CB and Patel, A and Porsteinsson, AP and Sabbagh, M},
title = {Targeted Treatment of Agitation in Alzheimer's Dementia: Prioritizing Function and Safety Over Sedation and Other Serious Harms.},
journal = {The primary care companion for CNS disorders},
volume = {28},
number = {5},
pages = {},
doi = {10.4088/PCC.haadachi2603},
pmid = {42771693},
issn = {2155-7780},
mesh = {Humans ; *Alzheimer Disease/complications/drug therapy ; *Psychomotor Agitation/drug therapy/etiology/therapy ; Primary Health Care ; *Hypnotics and Sedatives/therapeutic use/adverse effects ; *Antipsychotic Agents/therapeutic use/adverse effects ; },
abstract = {Agitation is a common and clinically significant neuropsychiatric condition in Alzheimer's dementia. Clinicians across the spectrum of care settings frequently encounter agitation but often lack practical clinical guidance. In April 2026, a consensus panel of clinical experts reviewed the literature and developed guidance for managing agitation in Alzheimer's dementia. The panel emphasized the critical role of primary care in agitation management and discussed different treatment approaches for optimizing patient and caregiver outcomes. Treatment should prioritize reduction of patient and caregiver distress and preservation of function rather than mere sedation. Discussion of neurobiology focused on the evolving models of frontal-limbic imbalance as the key driver of agitation in progressing Alzheimer's disease and implications for pharmacologic selection. The panel reviewed evidence on safety and efficacy of pharmacologic agents commonly used in agitation management and concluded that efficacy and safety profiles should guide clinical decision-making. The panel recommended conducting a behavioral assessment using validated tools, ruling out reversible causes, and using nonpharmacologic interventions as the first-line approach prior to starting pharmacologic treatment. Finally, setting-specific considerations were discussed. These recommendations complement prior guidance with a primary-care clinical decision pathway that matches treatment to the neurobiology of agitation and to comparative safety profiles, and that extends to the assessment, documentation, and coding clinicians need at the point of care. The goal is to help clinicians select evidence-based interventions for agitation in Alzheimer's dementia that prioritize safety, alertness, functional engagement, and caregiver well-being while minimizing the serious harms that have historically accompanied off-label management in this population, including excess mortality, cerebrovascular events, cognitive impairment, falls, and sedation. Prim Care Companion CNS Disord 2026;28(5):haadachi2603.},
}

Humans
*Alzheimer Disease/complications/drug therapy
*Psychomotor Agitation/drug therapy/etiology/therapy
Primary Health Care
*Hypnotics and Sedatives/therapeutic use/adverse effects
*Antipsychotic Agents/therapeutic use/adverse effects

@article {pmid42772203,
year = {2026},
author = {Miceli, F and Soldovieri, MV and Barrese, V and Taglialatela, M},
title = {Kv7 channels as pharmacological targets for central nervous system diseases.},
journal = {Pharmacological reviews},
volume = {78},
number = {6},
pages = {100153},
doi = {10.1016/j.pharmr.2026.100153},
pmid = {42772203},
issn = {1521-0081},
abstract = {Neuronal Kv7 (also known as KCNQ) voltage-gated potassium channels are key regulators of membrane excitability, primarily through their contribution to the M-current, a slowly activating and noninactivating potassium conductance that stabilizes the resting membrane potential and limits repetitive firing. Given the central role of the M-current in regulating critical central nervous system functions, it is not surprising that Kv7 channel dysfunction contributes to the onset and progression of a wide range of neuropsychiatric disorders, and that Kv7 channels are primary targets for pharmacological intervention in all these conditions. In this review, we provide a comprehensive overview of the physiological roles of neuronal Kv7 subunits (Kv7.2-Kv7.5) with particular emphasis on their expression patterns during development and across distinct neuronal populations. We also discuss the complex regulatory mechanisms governing Kv7 channel expression, trafficking, and function, including modulation by intracellular signaling pathways and interacting proteins. Particular attention is devoted to the involvement of Kv7 channel dysfunction in epileptic encephalopathies, pain syndromes, and neuropsychiatric conditions, as well as neurodegenerative disorders such as Alzheimer and Parkinson disease, where altered neuronal excitability is a common pathogenic hallmark. Furthermore, we examine the evolving pharmacological landscape of Kv7 channel modulators, from first-generation openers such as retigabine to next-generation agents, repurposed drugs, natural products, and Kv7 modulators currently in clinical development, highlighting both their therapeutic promise and existing challenges. Collectively, available evidence identifies Kv7 channels as versatile and highly attractive pharmacological targets for the treatment of central nervous system disorders characterized by maladaptive changes in neuronal excitability. SIGNIFICANCE STATEMENT: Kv7 channels are central regulators of neuronal excitability and are increasingly recognized as key therapeutic targets in multiple central nervous system disorders. Advancing our understanding of their pathophysiological role may enable the development of more selective and effective treatments for diseases driven by maladaptive changes in neuronal excitability.},
}

@article {pmid42773087,
year = {2026},
author = {Ritchie, M and Hussen, K and Langford, O and Donohue, MC and Sano, M and Grill, JD and Aisen, P and Sperling, R and Raman, R},
title = {Research satisfaction among participants in a preclinical Alzheimer's disease trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71852},
pmid = {42773087},
issn = {1552-5279},
support = {946223//American Heart Association/ ; U24AG053798//the NIA/ ; R01 AG063689/AG/NIA NIH HHS/United States ; U19AG010483/AG/NIA NIH HHS/United States ; U24AG057437/AG/NIA NIH HHS/United States ; //Eli Lilly/ ; //the Alzheimer's Association/ ; //the Accelerating Medicines Partnership/ ; //Foundation for the National Institutes of Health/ ; //Davis Alzheimer Prevention Program/ ; //Yugilbar Foundation/ ; //anonymous foundation/ ; //GHR Foundation/ ; //Additional private donors to Brigham and Women's Hospital, with in-kind support from Avid Radiopharmaceuticals, Cogstate, Albert Einstein College of Medicine and the Foundation for Neurologic Diseases/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; Female ; Male ; Aged ; Surveys and Questionnaires ; *Patient Satisfaction ; Motivation ; },
abstract = {INTRODUCTION: Empirical data capturing participants' experiences in preclinical Alzheimer's disease (AD) trials are limited. We examined participant responses on a Research Satisfaction Survey (RSS) from the Anti-Amyloid Treatment in Asymptomatic AD Study.

METHODS: Participants completed the RSS at week 0, 48, 108, 168, and 240. We examined potential differences in responses by baseline participant characteristics and trial completion status.

RESULTS: RSS scores were high, with > 90% of participants responding positively to all satisfaction items. Across timepoints, altruistic motivations were most frequently affirmed, while study design elements were most frequently disfavored. Affirmation of social motivations increased over time. Participants who responded "not satisfied" at baseline to repeating their decision to enroll had higher odds of study discontinuation than those who responded "satisfied" (1.99; 95% confidence interval [CI]:1.24, 3.19).

DISCUSSION: An RSS captures participant experiences in a preclinical AD trial, can guide decisions on study design features, and may identify those at risk for loss to follow-up.},
}

Humans
*Alzheimer Disease/drug therapy/psychology
Female
Male
Aged
Surveys and Questionnaires
*Patient Satisfaction
Motivation

@article {pmid42774120,
year = {2026},
author = {Gong, C},
title = {Implications of pentose phosphate metabolism and astrocyte co-expression patterns in the pathogenesis of Alzheimer's disease: evidence from artificial intelligence-driven omics and clinical validation.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1887060},
pmid = {42774120},
issn = {1662-4548},
abstract = {BACKGROUND: Metabolic reprogramming in glial cells is increasingly recognized as a pivotal factor in the pathogenesis of AD. While both the pentose phosphate pathway (PPP), a crucial metabolic route for redox balance and biosynthesis, and astrocyte reactivity are implicated in AD, their integrated molecular interaction between processes remains largely uncharted.

METHODS: We employed an integrated multi-omics and artificial intelligence (AI) framework. First, we applied the Limma, WGCNA, and xCell algorithms to bulk RNA-seq profiles from the hippocampus of AD patients to identify a gene signature linking the PPP and astrocyte reactivity (PA). This signature was then used to construct a diagnostic model via an explainable machine learning pipeline and to stratify patients into molecular subtypes through consensus clustering. The central hub gene of this PA-associated signature was subsequently validated using spatially and temporally resolved single-cell data from the AD hippocampus. An AI-based drug-repurposing screen (Drugreflector) and molecular docking simulations were used to identify natural compounds targeting this hub gene for the treatment of AD. Finally, the dysregulation of this target was confirmed by quantifying its expression in peripheral blood samples from a clinical AD cohort.

RESULTS: We identified eight PA-associated gene signatures in AD patients that can help elucidate the pathogenesis and molecular stratification. HDAC3 was identified as the central pathogenic hub, mainly distributed in astrocytes. Through drug screening, nervonic acid was identified as a potential therapeutic agent, showing a high binding affinity to HDAC3. Clinical validation confirmed elevated HDAC3 levels in AD patients.

CONCLUSION: Our study reveals a novel PA-associated molecular axis in AD, with HDAC3 serving as a central epigenetic-metabolic regulator within astrocytes. This co-expression axis provides a framework for patient subtyping, offers a promising diagnostic biomarker, and identifies a potential therapeutic target for AD.},
}

@article {pmid42775668,
year = {2026},
author = {Yin, Y and Li, Z},
title = {Mitochondrial Fusion and Fission in Age-Related Cardio-Cerebral Diseases: Mechanisms and Interventions.},
journal = {Aging cell},
volume = {25},
number = {10},
pages = {e70729},
pmid = {42775668},
issn = {1474-9726},
support = {2023JH2/101700204//The Science and Technology Program Joint Program of Liaoning Province (Project of Fundamental Research for Application)/ ; },
mesh = {Humans ; *Mitochondrial Dynamics/drug effects ; *Aging/metabolism/pathology ; Animals ; *Cardiovascular Diseases/metabolism/pathology ; *Cerebrovascular Disorders/metabolism/pathology ; *Mitochondria/metabolism ; },
abstract = {Mitochondria play a crucial role in cellular energy metabolism. The heart and brain require a continuous and stable energy supply. Energy production strongly depends on proper mitochondrial function. Mitochondrial fusion and fission, known as "plasticity", are vital for maintaining the normal physiological function of cells. Recent studies have shown that impaired mitochondrial dynamics are present in many aging-related diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and atherosclerotic cardio-cerebrovascular disease. The role of impaired mitochondrial dynamics in the pathophysiological process of aging-related diseases is being actively researched. We discovered that targeting proteins related to mitochondrial dynamics, especially those involved in fission and fusion, may offer new treatment strategies for these diseases. Various approaches, including aerobic interval and treadmill training and the use of drugs such as the antidiabetic agents metformin and dapagliflozin, the antihypertensive agent irbesartan, and certain traditional Chinese medicine components, have shown potential in alleviating imbalances in mitochondrial dynamics in aging-related cardio-cerebrovascular diseases. In this review, we systematically summarize recent research on alterations in mitochondrial dynamics in age-related cardio-cerebral diseases and explore therapeutic strategies targeting these alterations, which may offer new directions for improving cardiac and brain health and guiding clinical practice.},
}

Humans
*Mitochondrial Dynamics/drug effects
*Aging/metabolism/pathology
Animals
*Cardiovascular Diseases/metabolism/pathology
*Cerebrovascular Disorders/metabolism/pathology
*Mitochondria/metabolism

@article {pmid42777020,
year = {2026},
author = {Wang, D and Yan, S and Zhou, R and Li, Y and Liu, L and Wei, Y and Wang, D and Yao, H and Zhou, B and Lu, J and Wang, P and Liao, Z and Chen, Y and Zhang, X and Han, Y and Yu, C and Zhao, K and Liu, Y and , },
title = {Beyond statistical thresholds: Mapping sequential ATN cascade transitions via brain structural topography in Alzheimer's disease.},
journal = {Science advances},
volume = {12},
number = {39},
pages = {eaef3787},
pmid = {42777020},
issn = {2375-2548},
mesh = {*Alzheimer Disease/metabolism/pathology/diagnostic imaging ; Humans ; *Brain/pathology/metabolism/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Proteomics/methods ; Neuroimaging/methods ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease is widely conceptualized as a biological continuum initiated by amyloid-β (Aβ) accumulation, followed by tau aggregation and neurodegeneration. Although the ATN framework is commonly used to define disease stages, its static biomarker categories may not fully capture the dynamic pathological transitions that determine the optimal window for anti-Aβ therapies. Here, we introduce a Biological Continuum framework that distinguishes dynamic pathological cascades from static biomarker categories. Using neuroimaging-derived brain network topology, we identify four reproducible subgroups that exhibit distinct biological processes, biomarker signatures, and longitudinal cognitive trajectories. Integrated proteomic analyses suggest that these subgroups reflect sequential molecular transitions corresponding to early vulnerability, initiation, amplification, and terminal stages. Post hoc analysis indicates that slower cognitive decline after amyloid-targeting treatment was observed mainly in the initiation stage group. These findings provide a biologically grounded stratification system that captures disease dynamics overlooked by threshold-based models and offers mechanistic insight into the timing of anti-Aβ therapies.},
}

*Alzheimer Disease/metabolism/pathology/diagnostic imaging
Humans
*Brain/pathology/metabolism/diagnostic imaging
Amyloid beta-Peptides/metabolism
Biomarkers/metabolism
Proteomics/methods
Neuroimaging/methods
tau Proteins/metabolism

@article {pmid42777389,
year = {2026},
author = {Imbimbo, BP and Pomara, N and Pini, L and Frederiksen, KS},
title = {Repeated clinical trial failures in Alzheimer's disease: The pitfalls of pursuing epidemiological associations.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {204},
number = {},
pages = {119943},
doi = {10.1016/j.biopha.2026.119943},
pmid = {42777389},
issn = {1950-6007},
abstract = {Interventions for Alzheimer's disease (AD) have repeatedly been advanced from epidemiological associations, biological hypotheses and preclinical findings, yet many have failed in randomized trials and some have produced signals of clinical worsening. We examine illustrative successful and unsuccessful programs across infectious, inflammatory, metabolic, lipid, iron, dietary, hormonal and amyloid domains to determine what they reveal about causality and therapeutic translation. Negative results may indicate a non-causal or poorly specified target, but may also reflect inadequate central nervous system exposure, target engagement, disease-stage alignment, biomarker selection, population representativeness, statistical power, outcome selection or trial design. More informative programs distinguish prevention from symptomatic treatment, confirm AD pathology, establish central exposure and interpret target engagement together with clinical and functional outcomes rather than treating biomarker movement as a surrogate for benefit. We propose a causal-validation framework integrating convergent human evidence, mechanistic direction, central target engagement, supportive downstream biology, stage-appropriate and inclusively validated populations, and adequate design and power. Applying this framework before phase 3 testing should improve target selection, sharpen interpretation of negative trials and reduce costly late-stage failure.},
}

@article {pmid42761709,
year = {2026},
author = {Shahzad, M and Mushtaq, A and Rochais, C and Naseer, MM},
title = {Isatin derivatives as potent cholinesterase inhibitors: recent developments and future challenges.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42761709},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and neuronal loss, primarily associated with β-amyloid plaque deposition, tau hyperphosphorylation, and cholinergic dysfunction. Since the disruption of cholinergic neurotransmission is a key pathological feature of AD, the cholinesterase (ChE) inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) remain the mainstay of symptomatic treatment by enhancing synaptic acetylcholine levels. However, the currently approved small molecules, including tacrine, donepezil, rivastigmine, and galantamine, are limited by their modest efficacy, poor selectivity, and adverse effects, necessitating the development of improved therapeutic agents. Among emerging scaffolds, isatin (1H-indole-2,3-dione) has attracted considerable research attention owing to its structural versatility, synthetic accessibility, and favorable pharmacological properties. Recent studies have reported diverse isatin-based derivatives, including hydrazones, Schiff bases, thiosemicarbazones, spirooxindoles, and molecular hybrids, exhibiting potent AChE and BChE inhibitory activities, often in the submicromolar or nanomolar ranges. Structure-activity relationship studies have revealed the critical influence of electronic effects, linker optimization, N-substitution, and molecular hybridization on inhibitory potency and selectivity. This review summarizes the most promising isatin-based cholinesterase inhibitors reported from 2020 to the present, highlighting their biological activities, structure-activity relationships, and potential for the development of next-generation anti-Alzheimer therapeutics.},
}

@article {pmid42763072,
year = {2026},
author = {Shehu, K and Onimisi, OB and Bunza, HA and Umar, SM and Oyem, JC and Adewumi, TA},
title = {Prenatal origins of neurodegeneration: The role of maternal immune activation in Alzheimer's and Parkinson's pathobiology.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116029},
doi = {10.1016/j.expneurol.2026.116029},
pmid = {42763072},
issn = {1090-2430},
abstract = {Recent evidence suggests that prenatal environmental factors, particularly maternal infection or maternal immune activation (MIA), may influence the progression of brain aging and lifetime risk for neurodegenerative disorders. The hypothesis is that even a short-lived inflammatory event during pregnancy may leave a lasting imprint on the developing brain and immune system of the fetus, such that aging or subsequent insults may later unmask neurodegenerative disorders. Support for this hypothesis comes largely from animal studies, where gestational inflammation has been shown to potentiate the onset of Alzheimer's and Parkinson's diseases (AD/PD), by increasing amyloid/tau pathology, reducing synaptic connections, and damaging nigrostriatal dopaminergic neurons. We review convergent mechanisms, including microglial priming, chronic cytokine excess, oxidative stress, epigenetic marks and proteostatic deficits, through which maternal immune activation may embed a latent "hit" that synergizes with aging to precipitate AD or PD. Furthermore, we appraise experimental models and available human data linking MIA to AD versus PD, noting shared and distinct pathways. Despite growing preclinical evidence, translation to human cohorts remains limited by heterogeneity in MIA exposure timing and outcome measures. An understanding of MIA's impact on neurodegeneration could suggest preventive strategies and interventions for early diagnosis and treatment.},
}

@article {pmid42763350,
year = {2026},
author = {Duan, X and Chen, Z and Tong, X and Li, X and Liu, Z and Yang, Y and Liu, X and Liu, W},
title = {Irisin-BDNF axis mediates muscle-brain communication: a complete molecular cascade and potential bidirectional feedback from peripheral activation to central protection.},
journal = {Biogerontology},
volume = {27},
number = {5},
pages = {},
pmid = {42763350},
issn = {1573-6768},
support = {Grant No. 2026JJ90271//Natural Science Foundation of Hunan Province/ ; },
mesh = {Humans ; *Brain-Derived Neurotrophic Factor/metabolism ; *Fibronectins/metabolism ; Animals ; *Brain/metabolism ; *Muscle, Skeletal/metabolism ; *Alzheimer Disease/metabolism ; Myokines ; Signal Transduction ; Feedback, Physiological ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive decline, with core pathological mechanisms including β-amyloid (Aβ) deposition, tau protein hyperphosphorylation, neuroinflammation, and impaired synaptic plasticity. Although exercise has neuroprotective effects, the molecular mechanisms by which it mediates peripheral-central communication remain unclear. The concept of the 'muscle-brain dialogue' offers a new perspective on this process. irisin, secreted by skeletal muscle in response to exercise, forms a molecular link between peripheral exercise and central neuroprotection by specifically regulating brain-derived neurotrophic factor (BDNF). This review summarizes the molecular cascade mechanisms of the irisin-BDNF axis in mediating the muscle-brain dialogue: Irisin is synthesized via the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)/fibronectin domain-containing protein 5 (FNDC5) pathway. Current evidence suggests that peripheral irisin may communicate with the central nervous system through mechanisms related to the blood-brain barrier, including potential αVβ5 integrin-mediated interactions, thereby participating in the regulation of BDNF. As a core effector molecule, BDNF improves cognitive decline in AD by enhancing neuroplasticity, reducing Aβ deposition, inhibiting tau hyperphosphorylation, and alleviating neuroinflammation. However, oxidative stress and mitochondrial dysfunction associated with AD pathology negatively regulate this axis, creating a vicious cycle. Therefore, this paper explores potential intervention strategies and the prospects for future translational research, including upstream exercise interventions, midstream barrier-crossing enhancing peptides, and downstream small-molecule TrkB agonists. Targeting this axis provides a new theoretical foundation and translational direction for the early prevention and treatment of AD, as well as for drug development.},
}

Humans
*Brain-Derived Neurotrophic Factor/metabolism
*Fibronectins/metabolism
Animals
*Brain/metabolism
*Muscle, Skeletal/metabolism
*Alzheimer Disease/metabolism
Myokines
Signal Transduction
Feedback, Physiological

@article {pmid42763962,
year = {2026},
author = {Ye, J and Yin, S and Lin, Y and Yang, S and Ma, L and Wang, Y and Gao, K and Wang, Y and Yang, X and Yang, Z and Wang, N and Liu, H and Xu, S and Cui, W and Zhang, B},
title = {Substituted methyl acridone-carboxylate derivatives as CD1/CD2 dual-targeting HDAC6 inhibitors to ameliorate the pathological phenotype of Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {320},
number = {},
pages = {119350},
doi = {10.1016/j.ejmech.2026.119350},
pmid = {42763962},
issn = {1768-3254},
abstract = {Histone deacetylase 6 (HDAC6) has emerged as a promising target for Alzheimer' disease (AD). Although most reported HDAC6 inhibitors were designed to target CD2 catalytic domain, recent studies highlighted the functional importance of CD1 domain for the regulation of AD-related substrates. In this study, a series of substituted methyl acridone-carboxylate derivatives bearing a methyl ester moiety were discovered as CD1/CD2 dual-targeting HDAC6 inhibitors. The leading compound 6c could direct bind to HDAC6, and selectively inhibits HDAC6 with a high affinity in vitro. Molecular docking analysis revealed that 6c forms non-chelating coordination interactions with the zinc ions in both CD1 and CD2 domains of HDAC6. 6c inhibited Aβ oligomer-induced microtubule depolymerization and microglial phagocytic impairments in vitro. Furthermore, 6c effectively prevented HDAC6-driven α-tubulin and Hsp90 deacylation, as well as cognitive impairments in Aβ1-42 oligomer-treated mice. Combined with the acceptable physicochemical properties and promising biosafety of 6c, this study suggested that substituted methyl acridone-carboxylate derivatives, as CD1/CD2 dual-targeting HDAC6 inhibitors, might be developed as a novel lead drug for the treatment of AD.},
}

@article {pmid42764767,
year = {2026},
author = {Wenxin, S and Youmao, Z and Wenhua, H},
title = {Basic Research on the Lymphatic System and Exploratory Research in LVA Surgery for Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050503391260907045733},
pmid = {42764767},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive decline. Its characteristic pathological features include Aβ plaque deposition and abnormal tau protein aggregation. Biomarker testing has improved AD diagnosis. However, current treatments are primarily symptomatic, and no effective therapies are available to slow disease progression.

MATERIALS AND METHODS: In this review, PubMed, CNKI, Wanfang Data, and the Chinese Medical Journal Full-text Database were searched using core terms including lymphatic system, Alzheimer's disease, and deep cervical lymphatic-venous anastomosis with supplementary synonyms. After deduplication and two-round screening, irrelevant, duplicate, low-quality, and non-full-text articles were excluded, and eligible literature was systematically summarized.

RESULTS: The proposal of the glymphatic system has refined the theory of cerebral fluid circulation and waste clearance. Its dysfunction is closely associated with neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD), providing a novel target for AD treatment. Deep cervical Lymphatic-Venous Anastomosis (LVA), as an emerging surgical approach with potential to alleviate AD symptoms, has been initially validated for its short-term efficacy. However, it is still in the early stage of clinical exploration, and further systematic research is required for its successful clinical translation.

DISCUSSION: The glymphatic system mediates brain fluid circulation and waste clearance, providing new insights into AD pathogenesis and treatment. Building on this understanding, deep cervical Lymphatic-Venous Anastomosis (LVA) has emerged as a promising surgical intervention to alleviate AD pathology. Nevertheless, the considerable technical demands and incompletely elucidated mechanism of LVA severely limit its clinical translation, rendering these challenges a central research priority.

CONCLUSION: Breakthroughs in the central lymphatic system have provided an important direction for exploring the pathological mechanisms of AD and developing innovative therapeutic strategies. Clarifying the theoretical basis and technical evolution of LVA surgery, as well as addressing relevant controversial issues, constitutes a key focus to advance the basic research and clinical translation of AD treatment.},
}

@article {pmid42764861,
year = {2026},
author = {Qin, F and Zhang, N and Jiang, Y and Xu, K and Xiong, Y and Liu, Y and Ouyang, Q and Liu, H and Dai, Y and Jiang, L and Zhao, Y and Li, H and Wang, L and Chen, Y and Hu, L and Bu, Q and Zhao, Y and Kuang, W and Qin, M and Cen, X},
title = {Neutrophil-mediated BDNF delivery for the treatment of moderate to severe Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {9},
pages = {6185-6202},
pmid = {42764861},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD), especially its moderate-to-severe stage (MSAD), remains a global health challenge with no disease-modifying therapies. Here, we identified a dual pathological signature in MSAD patients and murine models: a systemic pro-inflammatory milieu and critically reduced brain-derived neurotrophic factor (BDNF) levels in both the hippocampus and serum. To mitigate the decrease in BDNF, we developed an engineered neutrophil capsule, in which neutrophils carrying lipid nanoparticles encapsulating BDNF penetrated the brain and ameliorated cognitive capacity deficits in MSAD mice. The pro-inflammatory state in the MSAD brain facilitated neutrophil passage through the blood-brain barrier, and inflammatory mediators triggered the release of BDNF from the engineered neutrophils. Collectively, our findings show that engineered neutrophil-mediated brain delivery of BDNF efficiently reduces the amyloid-β plaque deposition in the hippocampus, leading to significantly improved learning and memory in MSAD mice. This study establishes neutrophil-mediated delivery as a paradigm strategy for MSAD, merging cell biology with nanotechnology to reverse neurodegeneration.},
}

@article {pmid42767717,
year = {2026},
author = {Maiese, K},
title = {Running out the clock: Circadian rhythm dysfunction in cognitive disease.},
journal = {International review of neurobiology},
volume = {190},
number = {},
pages = {231-306},
pmid = {42767717},
issn = {2162-5514},
support = {R01 NS053946/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; Animals ; *Chronobiology Disorders/metabolism/physiopathology ; *Circadian Rhythm/physiology ; *Cognitive Dysfunction/metabolism/physiopathology ; *Cognition Disorders/physiopathology/metabolism ; },
abstract = {Lifespan is increasing such that within a few decades approximately twenty percent of the world's population is expected to be greater than sixty years of age. In concert with global aging of the population, neurodegenerative disorders have become the leading cause of disability with dementia now the seventh leading cause of death worldwide. Despite multi-faceted treatment approaches for disorders of cognition that include Alzheimer's disease and multiple sclerosis, present therapies ultimately cannot halt disease progression and eventually cognitive impairment continues unabated. Furthermore, co-morbidities, such as metabolic disorders with diabetes mellitus, also lack strategies to prevent disease progression. Given these clinical challenges for cognitive loss, innovative avenues of investigation that involve mammalian chronobiology with circadian rhythm clock genes and related pathways of aging, cellular senescence, oxidative stress, metabolic dysfunction, sleep fragmentation, apolipoprotein E, programmed cell death, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), nicotinamide adenine dinucleotide, the gut microbiota, and glucagon-like peptide-1 receptor agonism may offer exceptional promise for forging new strategies for cognitive disease treatment. These pathways are intimately linked to circadian rhythm processes, are complex in generating biological outcomes, can broadly influence clinical translation of both short- and long-term considerations for cognitive disease care, and necessitate dissection of their precise regulatory mechanisms with the benefit from early diagnostic platforms as well as artificial intelligence and machine learning applications to foster translation of these pathways into effective clinical treatments.},
}

Humans
Animals
*Chronobiology Disorders/metabolism/physiopathology
*Circadian Rhythm/physiology
*Cognitive Dysfunction/metabolism/physiopathology
*Cognition Disorders/physiopathology/metabolism

@article {pmid42756207,
year = {2026},
author = {Panabakam, N and Elangovan, K and Seerangan, K and Manogaran, N and Malleeswaran, K and Yogarayan, S},
title = {Alzheimer's disease detection from structural brain MRI using FFA U-Net segmentation and transfer learning.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1871982},
pmid = {42756207},
issn = {1662-4548},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to a gradual decline in cognitive and memory function. Multimodal neuroimaging, particularly magnetic resonance imaging (MRI), has become a central diagnostic tool for tracking disease progression, supporting diagnosis, treatment planning, and follow-up monitoring. Manual delineation of brain structures by clinicians remains time-consuming and labor-intensive, and computer-assisted segmentation is complicated by spatial and structural variability as well as intensity inhomogeneity across images. This study proposes an integrated framework for automated brain image segmentation and AD classification to address these challenges.

METHODS: The framework combines a modified U-Net architecture, termed FFA U-Net, with a fine-tuned VGG16 classifier. FFA U-Net incorporates a residual inception module and a feature fusion attention mechanism into the standard U-Net backbone to perform end-to-end brain tissue segmentation. Segmented outputs are subsequently passed to the fine-tuned VGG16 model for classification of AD status. The framework was evaluated on two datasets, ADNI (843 images) and OASIS (416 images), using subject-wise, non-overlapping training, validation, and test splits to prevent data leakage.

RESULTS: The proposed framework achieved a segmentation Dice Similarity Coefficient (DSC) of 0.929 and a classification accuracy of 98.90%, based on a single data split. These results were consistent across both the ADNI and OASIS datasets, indicating competitive segmentation and classification performance.

DISCUSSION: The findings suggest that combining attention-augmented segmentation with transfer learning-based classification can effectively support automated AD detection from structural MRI, potentially reducing the manual burden on clinicians. As results are based on a single split, further validation using cross-validation or independent cohorts is warranted to confirm robustness and generalizability. The framework should currently be regarded as an experimental research tool that requires additional clinical validation before deployment in practice.},
}

@article {pmid42756662,
year = {2026},
author = {Mirshekar, MA and Nadi, F and Fanaei, H and Chahkandi, M},
title = {Modulation of spatial learning and memory by cannabinoid-estrogen interaction in an AD-like cognitive impairment: The role of cannabinoid receptors and BDNF protein.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {780-789},
pmid = {42756662},
issn = {2667-2421},
abstract = {Alzheimer's disease (AD) is an increasingly prevalent neurodegenerative disorder worldwide, with women showing a higher risk of developing the disease. The decline in steroid hormones after menopause may contribute to the increased susceptibility of women to neurodegenerative conditions. In parallel, cannabis-derived compounds have been reported to alleviate certain symptoms associated with neurological disorders. The present study was designed to investigate the effects of marijuana extract on cognitive impairment and hippocampal molecular markers in an ovariectomized AD-like rat model, and to evaluate whether co-administration with estradiol modifies these effects. The marijuana extract used in this study was characterized by HPLC and was found to contain 8.5% Δ9-THC. AD-like cognitive impairment pathology was induced by intra-hippocampal administration of Aβ25-35 in OVX rats. Animals were treated with marijuana extract (60 mg/kg/day, corresponding to approximately 5.1 mg/kg/day Δ9-THC) either alone or in combination with 17β-estradiol (1 mg/kg every 4 days) for 28 days. Cognitive performance was evaluated using the Morris water maze (MWM). In addition, hippocampal CB1/CB2 receptor expression and BDNF protein levels were measured to examine potential molecular associations. Our findings showed that chronic administration of the marijuana extract improved Aβ25-35-induced deficits in spatial learning and memory. Alterations in CB1 receptor expression and BDNF levels accompanied these behavioral effects. Notably, co-treatment with estradiol did not produce a synergistic effect, suggesting a complex interaction between cannabinoid-related and estrogen-related signaling pathways. These preclinical findings suggest that a THC-standardized marijuana extract may exert neuroprotective-like effects in an AD-like cognitive impairment model. However, because the extract was not fully phytochemically characterized and the mechanistic analyses were correlational, the results should be interpreted cautiously. Further studies are needed to clarify the underlying mechanisms and translational relevance of these findings.},
}

@article {pmid42756830,
year = {2026},
author = {Li, X and Miao, Z and Bi, J and Zhang, J and Wang, N},
title = {Sucralose Induces Neurobehavioral Alterations and Exacerbates Alzheimer's Disease-Like Phenotypes in Zebrafish Models.},
journal = {ACS omega},
volume = {11},
number = {36},
pages = {54169-54186},
pmid = {42756830},
issn = {2470-1343},
abstract = {Artificial sweeteners are widely consumed, yet their potential neurotoxic effects remain poorly understood. Using sucralose (SUC) as a model compound, this study develops an approach to rapidly screen the neurotoxicity of artificial sweeteners and explore their potential associations with neurodegenerative-like processes, especially Alzheimer's disease (AD)-like phenotypes. SUC is minimally absorbed and metabolized by mammals, leading to its widespread presence in the environment. Here, we integrate high-throughput behavioral phenotyping in larval zebrafish with targeted analyses in adult and AD transgenic models, employing a "behavioral phenoblast" strategy adapted from prior large-scale sleep-wake drug screens. SUC effects were evaluated across a broad concentration range (5 μg/L to 100 mg/L), covering low-dose to high-dose exposure conditions. Hierarchical and K-means clustering revealed that SUC's behavioral signatures closely resembled those of compounds associated with neurodegenerative risks. To validate these findings, adult zebrafish were exposed to SUC within the Acceptable Daily Intake (ADI) range (1-100 mg/L) for 3 months, resulting in dose-dependent increases in anxiety-like behaviors and impairments in learning and memory. Notably, treatment of transgenic zebrafish expressing human misfolded Aβ protein with SUC exacerbated Aβ-related pathological phenotypes in a dose-dependent manner. These findings highlight the need for further investigation into the long-term neurological impacts of artificial sweeteners and provide a methodological framework for evaluating the potential health risks of artificial sweeteners.},
}

@article {pmid42757822,
year = {2026},
author = {Gaber, DA},
title = {Engineering centrifugally spun nanofibrous matrices as high-performance transdermal patches for accelerated Alzheimer's treatment.},
journal = {Journal of biomaterials science. Polymer edition},
volume = {},
number = {},
pages = {1-26},
doi = {10.1080/09205063.2026.2734516},
pmid = {42757822},
issn = {1568-5624},
abstract = {This study aimed to develop and optimize a centrifugally spun polycaprolactone/poly(vinyl alcohol) (PCL/PVA) nanofibrous transdermal patch containing polyethylene glycol 400 (PEG 400) and oleic acid to improve rivastigmine delivery for the long-term management of Alzheimer's disease. Rivastigmine-loaded nanofibrous patches were fabricated by centrifugal spinning and characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR). Mechanical properties, drug release, ex vivo skin permeation and deposition, dermal irritation, pharmacokinetics in New Zealand White rabbits, and stability were systematically evaluated. The optimized formulation (F5) produced uniform, bead-free nanofibers (1.7 ± 0.3 μm) with rivastigmine molecularly dispersed in an amorphous state within the polymeric matrix. The patch exhibited favorable mechanical properties, sustained drug release, enhanced ex vivo skin permeation (0.50 ± 0.04 mg/cm[2] at 24 h), and increased drug deposition within the viable epidermis and dermis, indicating cutaneous reservoir formation. Dermal irritation was negligible (Primary Irritation Index = 0.08). Pharmacokinetic studies demonstrated prolonged systemic absorption (Tmax = 6.0 ± 1.0 h) and approximately five-fold greater systemic exposure (AUC0-∞ = 345 ± 28 ng·h/mL) than the oral formulation (67 ± 9 ng·h/mL, p < 0.05).The optimized centrifugally spun nanofibrous patch provided sustained rivastigmine delivery, excellent dermal biocompatibility, enhanced skin deposition, and improved systemic bioavailability, supporting its potential as a scalable transdermal platform for long-term Alzheimer's disease therapy.},
}

@article {pmid42758107,
year = {2026},
author = {Abdanipour, A and Nikfar, A and Feizi, H},
title = {Selegiline induces neuroprotection via PGC-1α/Nrf2 gene upregulation in H2O2 -treated hippocampal-derived neural stem/progenitor cells.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {72},
number = {5},
pages = {47-53},
doi = {10.14715/cmb/2026.72.5.7},
pmid = {42758107},
issn = {1165-158X},
mesh = {*Selegiline/pharmacology ; *Hydrogen Peroxide/pharmacology/toxicity ; Animals ; *NF-E2-Related Factor 2/genetics/metabolism ; *Hippocampus/cytology ; *Neural Stem Cells/drug effects/metabolism/cytology ; *Up-Regulation/drug effects ; Apoptosis/drug effects ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; *Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; Oxidative Stress/drug effects ; Rats ; Cells, Cultured ; Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; *Neuroprotection/drug effects ; },
abstract = {Oxidative stress mediated by reactive oxygen species (ROS) is a major contributor to the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, multiple sclerosis, and amyotrophic lateral sclerosis. Selegiline, a monoamine oxidase B inhibitor, has been reported to exert neuroprotective effects, although its precise cytoprotective mechanisms remain unclear. In this study, we investigated the effects of selegiline on apoptosis, necrosis, and cell survival in hydrogen peroxide (H2O2)-treated hippocampal-derived neural stem/progenitor cells (HD-NSPCs) in vitro. Passage 3 HD-NSPCs were treated with varying concentrations of selegiline (10[-3] to 10[-9] M) prior to exposure to 125 μM H2O2. Cell viability was assessed using the MTT assay, while apoptosis and necrosis were evaluated using TUNEL and acridine orange/ethidium bromide staining, respectively. Real-time RT-PCR was performed to quantify mRNA levels of PGC-1α, Nrf2, and Bcl-2. Treatment with 10[-7] M selegiline significantly enhanced HD-NSC viability, reduced apoptotic and necrotic cell fractions, and upregulated PGC-1α, Nrf2, and Bcl-2 expression compared to untreated cells (P < 0.05). These findings suggest that selegiline mitigates oxidative stress-induced cytotoxicity by activating Nrf2/PGC-1α signaling and promoting anti-apoptotic gene expression, thereby preserving mitochondrial function and enhancing cell survival. Overall, selegiline may represent a promising therapeutic agent for protecting neural progenitor cells and alleviating neuronal damage in neurodegenerative disorders.},
}

*Selegiline/pharmacology
*Hydrogen Peroxide/pharmacology/toxicity
Animals
*NF-E2-Related Factor 2/genetics/metabolism
*Hippocampus/cytology
*Neural Stem Cells/drug effects/metabolism/cytology
*Up-Regulation/drug effects
Apoptosis/drug effects
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism
*Neuroprotective Agents/pharmacology
Cell Survival/drug effects
Oxidative Stress/drug effects
Rats
Cells, Cultured
Proto-Oncogene Proteins c-bcl-2/metabolism/genetics
*Neuroprotection/drug effects

@article {pmid42758114,
year = {2026},
author = {Ran, J and Wei, Q and Lu, T and Liao, X and Pang, X and Zhu, Q and Zhou, H and He, X},
title = {Cognitive-enhancing effects of a herbal combination on D‑galactose‑induced memory impairment.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {72},
number = {5},
pages = {1-6},
doi = {10.14715/cmb/2026.72.5.1},
pmid = {42758114},
issn = {1165-158X},
mesh = {Animals ; *Galactose ; *Memory Disorders/drug therapy/chemically induced ; Cognitive Enhancement ; Acetylcholinesterase/metabolism ; Male ; Mice ; Cholinesterase Inhibitors/pharmacology/therapeutic use ; Maze Learning/drug effects ; Signal Transduction/drug effects ; Malondialdehyde/metabolism ; Hippocampus/drug effects/pathology/metabolism ; Oxidative Stress/drug effects ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, for which effective pharmacological interventions remain limited. This study investigated the cognitive-enhancing effects of an optimized six‑herbal combination (HC) comprising Polygonati Rhizoma (PR), Lycium barbarum polysaccharides (LBPs), Green Tea (GT), Jujube Seeds (JS), Fructus hippophae (FH), and Mori Folium (MF). Using the Ellman method, we evaluated the acetylcholinesterase (AChE) inhibitory activities of individual herbs and HC. An L25(4[6]) orthogonal design was employed to determine the optimal proportions of the six herbs, with AChE inhibition as the evaluation index. The optimal HC composition (PR 9 g, LBPs 6 g, GT 3 g, JS 3 g, FH 3 g, MF 5 g) exhibited 88.11% AChE inhibition at 2000 μg/mL, which was significantly higher than that of any individual herb (p < 0.05). Network pharmacology analysis revealed 682 common targets between HC and AD, with significant enrichment in the PI3K‑Akt signaling pathway, lipid metabolism, and chemical carcinogenesis‑receptor activation pathways, suggesting multi‑target mechanisms of action. In a D‑galactose‑induced subacute aging mouse model (3.5 g·kg[-1], 70 days), HC treatment (0.75, 1.5, and 3.0 g·kg[-1], 28 days) significantly improved spatial learning and memory in the Morris water maze. Specifically, HC at 1.5 g·kg[-1] significantly reduced escape latency (p < 0.01 vs. D‑galactose group), increased superoxide dismutase (SOD) and glutathione (GSH) levels (p < 0.05), and decreased malondialdehyde (MDA) and monoamine oxidase (MAO) levels (p < 0.01), while ameliorating hippocampal neuronal damage, as confirmed by hematoxylin and eosin staining. These findings demonstrate that HC exhibits potent anti‑cholinesterase activity, modulates oxidative stress, and protects against neuronal injury, positioning it as a promising multi‑target botanical candidate for further development in the prevention and management of AD.},
}

Animals
*Galactose
*Memory Disorders/drug therapy/chemically induced
Cognitive Enhancement
Acetylcholinesterase/metabolism
Male
Mice
Cholinesterase Inhibitors/pharmacology/therapeutic use
Maze Learning/drug effects
Signal Transduction/drug effects
Malondialdehyde/metabolism
Hippocampus/drug effects/pathology/metabolism
Oxidative Stress/drug effects
*Drugs, Chinese Herbal/pharmacology/therapeutic use

@article {pmid42759232,
year = {2026},
author = {Pocknell, C and Dinius, C and Foley, R and Commins, S and McHugh Power, J and Roche, R},
title = {Tracing dementia: Reminiscence therapy in and from place.},
journal = {Health & place},
volume = {102},
number = {},
pages = {103744},
doi = {10.1016/j.healthplace.2026.103744},
pmid = {42759232},
issn = {1873-2054},
abstract = {Across different disciplines, there has been increasing interest in the relationships between early-stage dementia, place and different forms of treatment. Reminiscence therapy has demonstrated benefits in stalling the progression of dementia, especially in its early-stage, and within such therapies, relationships between place memory and the beneficial triggering effect of place-based events and personal narratives have become important aspects. Promoting physical activity outdoors is associated with better management of dementia that additionally recognises a potential role for meaningful local places and spaces. Much of this place-based research, including go-alongs, are informed by mobile methodologies, with new spatial technologies (beyond risk-informed tracking) having much potential when used directly with patients within and outside their home places. However, there remain questions about the feasibility of using such methodologies for the purposes of place-based intervention among individuals with early-stage dementia. We document a recent proof-of-concept study, AIM-WARM, that investigated the potential impact of combining the exercise of walking and reminiscence therapy, in early Alzheimer's disease groups, to explore how such technologically-enabled place-based tools worked. Instrumental and walkability measures were augmented by digital mapping and a spatial video app, Ubipix, to capture go-alongs across familiar routes traced out within the town of Maynooth (Ireland). Specific findings identified positive results in relation to four distinct aspects of the study: walkability, cognitive instruments, the capturing of place-traces and a positive narrative response to being and moving outdoors. Additional methodological reflection considered the value of go-alongs to capture traces of people's past within their current everyday neighbourhoods, to help better understand and represent the voice of people living with dementia within community settings.},
}

@article {pmid42759802,
year = {2026},
author = {Junwu, F and Xiangqian, R and Chengyong, Y and Dai, K and Wang, J and Xiang, X and Guoqing, Z},
title = {Alzheimer's disease-associated transcriptional signatures define prognostic subtypes in glioma.},
journal = {Brain research},
volume = {},
number = {},
pages = {150525},
doi = {10.1016/j.brainres.2026.150525},
pmid = {42759802},
issn = {1872-6240},
abstract = {BACKGROUND: Gliomas are molecularly heterogeneous central nervous system tumors with marked variation in clinical outcome. Alzheimer's disease (AD)-associated transcriptional alterations may capture neural and immune programs relevant to glioma biology, but they do not by themselves establish a direct mechanistic relationship between AD and glioma.

METHODS: AD-associated differentially expressed genes were identified from GSE132903 and evaluated in TCGA/GTEx and CGGA glioma datasets. Consensus clustering, enrichment analysis, Cox and LASSO modeling, immune deconvolution, and mutation analyses were performed. The incremental prognostic value of the AD-Driven score (ADDs) was tested after adjustment for age, sex, WHO grade, IDH status, 1p/19q codeletion, and MGMT promoter methylation. Protein-expression and glioma survival annotations for the 14 model genes were reviewed in the Human Protein Atlas (HPA).

RESULTS: We identified 470 CE-associated differentially expressed genes enriched in synaptic, calcium-signaling, and neurotransmitter pathways. A 14-gene ADDs model stratified survival in the discovery and validation cohorts. Among 554 complete cases with 147 deaths, continuous standardized ADDs remained associated with overall survival after molecular and clinicopathological adjustment (HR per SD = 1.76, 95 % CI 1.26-2.44, P = 0.0008), improving model fit (likelihood-ratio P = 0.0008) but only modestly increasing the C-index (0.876 to 0.880). HPA review provided directionally supportive glioma survival annotations for seven model genes.

CONCLUSION: The ADDs captures prognostically relevant neural and immune transcriptional variation in glioma and provides incremental information beyond established molecular variables when modeled continuously. The cross-cancer IMvigor210 analysis remains exploratory and does not establish prediction of immunotherapy benefit in glioma. HPA observations provide orthogonal public-database support for selected signature components, while independent tissue-based, mechanistic, and glioma-specific treatment-response validation remain necessary.},
}

@article {pmid42760588,
year = {2026},
author = {Abdelhamid, M and Padhi, P and Gifani, M and Beck, JS and Thomas, JP and Khadse, G and Kudela, C and Phillips, GJ and Kanthasamy, AG and Counts, SE},
title = {Bioengineered microbiotic levodopa therapy improves cognition and reduces pathology in a rat model of Alzheimer's disease.},
journal = {British journal of pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bph.70670},
pmid = {42760588},
issn = {1476-5381},
support = {R01AG060731//National Institutes of Health (NIH)/ ; U01AG074960//National Institutes of Health (NIH)/ ; //Johnny Isakson Endowed Chair, Coach Mark Rich Endowment/ ; //Georgia Research Alliance Eminent Scholar funds/ ; },
abstract = {BACKGROUND AND PURPOSE: Degeneration of the pontine noradrenergic and midbrain dopaminergic systems contributes to cognitive-behavioural disturbances during the prodromal stages of Alzheimer's disease (AD). We developed a genetically engineered, programmable probiotic Escherichia coli Nissle 1917 strain (EcN[rha] L-DOPA) capable of producing L-3,4-dihydroxyphenylalanine (L-DOPA) in a sustained and titratable manner, thus offering a novel gut-brain delivery mechanism to increase brain levels of noradrenaline and dopamine during the early stages of AD.

EXPERIMENTAL APPROACH: We replicated locus coeruleus (LC) projection system degeneration in AD by administering dopamine-β-hydroxylase IgG-saporin immunotoxin into the prefrontal cortex of 6-months-old Tg344-19 AD rats. The animals then received EcN[rha] L-DOPA/benserazide or placebo by daily gavage for 6 weeks. We assessed cognitive-behavioural function prior to postmortem assessments of amyloid-β plaque load, glial cell activation and neuronal and synaptic markers. Gut colonization, along with plasma and brain L-DOPA, dopamine, noradrenaline and metabolite levels, were also measured.

KEY RESULTS: EcN[rha] L-DOPA displayed stable gut colonization and resulted in sustained therapeutic levels of L-DOPA in plasma and brain, resulting in increased cortical and hippocampal noradrenaline levels. EcN[rha] L-DOPA reduced anxiety-like behaviour improved spatial and working memory. The treatment reduced forebrain Aβ plaque and MHC-II antigen-presenting microglial load. Additionally, EcN[rha] L-DOPA increased protein levels of the dendritic spine marker PSD95.

CONCLUSIONS AND IMPLICATIONS: This translational study suggests that EcN[rha] L-DOPA modifies AD by boosting brain catecholamine production, reducing Aβ accumulation and neuroinflammation, promoting synaptic health, and enhancing cognitive function. Collectively, these results highlight EcN[rha] L-DOPA as a promising preclinical engineered gut microbiome-based therapeutic strategy for early-stage AD.},
}

@article {pmid42754556,
year = {2026},
author = {Wiseman, FK},
title = {New mouse models for Down syndrome Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488873},
doi = {10.1177/13872877261488873},
pmid = {42754556},
issn = {1875-8908},
abstract = {In this issue Ishihara and colleagues report the development and characterization of new mouse models for Down syndrome Alzheimer's disease, the most commonly occurring genetic cause of dementia worldwide. These new models add to the growing portfolio of in vivo models of Down syndrome. In particular, the new Ts1Kei-APPswe/PS1[dE9] model may be highly useful for the study and identification of novel treatment targets for late onset myoclonic epilepsy of Down syndrome. This seizure disorder is a common comorbidity of Down syndrome Alzheimer's disease affecting around half of all people with the condition and is associated with particularly adverse clinical outcomes.},
}

@article {pmid42755290,
year = {2026},
author = {Xu, L and Wei, N and Ran, Y},
title = {The dynamic connectome in Alzheimer's disease: From static snapshots to a symphony in time-A hypothesis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488872},
doi = {10.1177/13872877261488872},
pmid = {42755290},
issn = {1875-8908},
abstract = {The static functional connectivity (sFC) model has established Alzheimer's disease (AD) as a large-scale brain network disorder, yet it rests on a questionable assumption of temporal stationarity. This assumption obscures the brain's intrinsic dynamics, which are essential for flexible cognition. Here, we advance the hypothesis that the core deficit in AD is not merely a weakening of average connections, but a fundamental loss of the brain's capacity for temporal coordination, adaptive reconfiguration, and metastable dynamics-a state we term dynamic network dysrhythmia. Synthesizing evidence from dynamic functional connectivity (dFC) studies across the AD continuum, from subjective cognitive decline to mild cognitive impairment and AD dementia, we argue that the AD brain exhibits a progressive collapse in temporal flexibility: reduced state transition frequency, diminished connectivity variability, and entrapment in inefficient network configurations. These dynamic abnormalities correlate with molecular pathology, structural disconnection, and domain-specific cognitive deficits, positioning dFC metrics as sensitive, systems-level digital biomarkers. We further outline methodological challenges and translational opportunities for dFC in early detection, prognostic stratification, and treatment monitoring. This hypothesis reframes AD from a static disconnection syndrome to a dynamic dysrhythmia, with profound implications for both mechanistic understanding and clinical practice.},
}

@article {pmid42756205,
year = {2026},
author = {Liu, D and Zhuo, Y and Chen, S and Wang, Y and Chen, X and Yao, Y},
title = {The role of apolipoprotein E4 on calcium homeostasis in primary hippocampal neurons: an in vitro study.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1845934},
pmid = {42756205},
issn = {1662-4548},
abstract = {BACKGROUND: We previously demonstrated that apolipoprotein E (apoE4) accelerates neurodegeneration in a transgenic mouse model, but the mechanism is still unclear. A previous study reported that death-associated protein kinase 1 (DAPK1) interacts with the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor, this DAPK1-NR2B interaction increases calcium intake in cells, leading to cell damage. As apoE4 is the strongest genetic risk factor for sporadic Alzheimer's disease (sAD) and calcium dyshomeostasis is a key driver of sAD-related neurotoxicity, the unclear mechanism linking apoE4 to calcium imbalance remains a critical gap in developing targeted therapies for sAD. Addressing this gap is urgent to advance our understanding of sAD pathogenesis and identify new therapeutic targets. Our study aimed to determine whether the neurotoxic effects of apoE4 are mediated by the interaction between DAPK-1 and the NMDA receptor NR2B subunit.

METHODS: Primary mouse hippocampal neurons were cultured with apoEs in the presence or absence of an NMDA receptor antagonist that preferentially targets NR2B-containing receptors. Intracellular calcium concentration, cell viability and the proteins related to calcium homeostasis were detected.

RESULTS: Cells treated with apoE4 showed increased levels of intracellular calcium and cell death. The expression of DAPK-1 and NR2B was up-regulated, and interacted with each other under the condition of ApoE4 culture.

CONCLUSION: Our study showed that apoE4 causes neurotoxicity by increasing intracellular calcium concentration. The possible mechanism of which was that apoE4 increased the expression of DAPK-1/NMDAR2B, and further promoted the interaction between the two. These results may provide new targets and ideas for the treatment of AD.},
}

@article {pmid42754545,
year = {2026},
author = {Nanna, MG and Cohen, AB and Erickson, AC and Sun, B and Rossi, R and Akman, Z and Krishnaswami, A and Damluji, AA and Leggett, CG and Staiger, DO and Agha, L},
title = {Days Alive at Home After Emergency Department STEMI Visits Among Medicare Beneficiaries With Dementia.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70705},
pmid = {42754545},
issn = {1532-5415},
support = {P30-AG021334//Johns Hopkins University Claude D. Pepper Older Americans Independence Center/ ; NIA P30-AG021334//Johns Hopkins University Claude D. Pepper Older Americans Independence Center/ ; K23-HL153771-01/HL/NHLBI NIH HHS/United States ; K76AG088428/AG/NIA NIH HHS/United States ; P01AG019783/AG/NIA NIH HHS/United States ; //American College of Cardiology Foundation/ ; /PCORI/Patient-Centered Outcomes Research Institute/United States ; P30AG021342//Yale Claude D. Pepper Older Americans Independence Center/ ; },
abstract = {BACKGROUND: As the population of older adults with Alzheimer's disease and related dementias (ADRD) increases, a growing number are presenting with acute cardiovascular events, including ST-elevation myocardial infarction (STEMI). Patient-centered outcomes following treatment for STEMI in this population are not well understood.

METHODS: This retrospective cohort study used Medicare fee-for-service claims from a 100% national sample to identify beneficiaries aged 65 years or older who presented to the emergency department (ED) with STEMI between 2017 and 2022 and underwent cardiac catheterization. Patients were stratified by ADRD status and nursing home admission source. The primary outcome was adjusted days alive at home in the year following the index ED visit. Secondary outcomes included 1-year survival, percent of alive days spent at home, and long-term nursing home care use (≥ 100 days). Multivariable linear regression models controlled for age, sex, and comorbidities.

RESULTS: Of 117,318 patients, 7348 (6.3%) had ADRD and 2617 (2.2%) were admitted from a nursing home. Among community-dwelling patients, those with ADRD had moderately lower adjusted days at home than those without ADRD (225.1 vs. 299.4; adjusted difference -37.8 days; 95% CI, -41.1 to -34.5), but more than half spent over 300 days at home. Among patients admitted from a nursing home, ADRD was associated with markedly worse outcomes (adjusted difference -71.9 days; 95% CI, -84.0 to -59.8), and 1-year survival was 42.4%.

CONCLUSION: Many community-dwelling older adults with ADRD experienced meaningful survival and time at home following cardiac catheterization for STEMI. Dementia status alone should not deter appropriate STEMI care. Treatment decisions should be individualized based on cognitive status, admission source, and patient goals.},
}

@article {pmid42754555,
year = {2026},
author = {Alcaide-Prados, MDC and Gómez-Moreno, G and Leizaola-Cardesa, IO and Moreu, G and Roa-López, A and Aguilar-Salvatierra, A},
title = {Periodontal disease and Alzheimer's disease: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488806},
doi = {10.1177/13872877261488806},
pmid = {42754555},
issn = {1875-8908},
abstract = {BackgroundPeriodontitis is a host-mediated inflammatory disease of microbial origin that results in the loss of periodontal attachment. Its effects are not limited to the oral cavity, as association with systemic diseases, including Alzheimer's disease (AD), has been widely reported.ObjectiveTo evaluate the evidence regarding the potential relationship between periodontitis and AD through a systematic review.MethodsA bibliographic search was conducted in PubMed, Scopus, and WOS. Studies published within the last five years evaluating the biological association between both diseases were selected. The methodological quality and risk of bias of the included studies were assessed using the NOS and ROBINS-I tool, according to the study design.ResultsEleven studies were included. Eight studies analyzed biological samples obtained from brain tissue, blood/serum, saliva, gingival crevicular fluid, and cerebrospinal fluid. Patients with AD exhibited higher levels of periodontopathogenic bacteria, such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia, and an association between bacterial load and systemic inflammatory markers. Although most studies reported an association between periodontitis and AD, the findings were not consistent across studies, as some failed to identify statistically significant differences. Periodontal treatment was associated with a reduction in the AD Score, a neuroimaging surrogate marker of preclinical AD, whereas no effect was observed on brain age gap.ConclusionsEvidence suggests a possible association between periodontitis and AD through inflammatory and neurodegenerative mechanisms. Methodological limitations and study heterogeneity preclude establishing causality, underscoring the need for longitudinal studies and alternative methodological approaches.},
}

@article {pmid42751437,
year = {2026},
author = {Zhao, G and Zhou, X and Yin, S and Xu, F and Xu, L and Wang, Q and Zhou, J and Liu, S},
title = {Seven-year follow-up demonstrating sustained survival following [125]I seed brachytherapy in an elderly patient with lip squamous cell carcinoma and Alzheimer's disease: A case report.},
journal = {Oncology letters},
volume = {32},
number = {5},
pages = {490},
pmid = {42751437},
issn = {1792-1082},
abstract = {Lip squamous cell carcinoma is a distinct subtype of oral malignancy. Surgical resection provides satisfactory local tumor control; however, it frequently compromises oral function, diminishes local sensation and disfigures facial contour-sequelae are disproportionately debilitating in elderly patients with multimorbidity. This study reported the case of an 80-year-old woman with Alzheimer's disease who presented with locally advanced lip squamous cell carcinoma (cT3N2bM0, stage IVA) and cervical lymph node metastases. Following multidisciplinary team evaluation, the patient was deemed unsuitable for curative surgical resection or definitive external-beam radiotherapy. Therefore, computed tomography (CT)-guided radioactive [125]I seed implantation, assisted by a three-dimensional (3D) printed template, was performed for both the primary lip tumor and the metastatic cervical nodes, with a prescribed dose of 140 Gy. Postprocedural dosimetric verification confirmed adequate target volume coverage. The patient achieved a durable clinical complete response, with remarkable tumor regression, preserved speech and swallowing function, and remains alive with overall survival exceeding 7 years. This case demonstrates the long-term efficacy and safety of the aforementioned minimally invasive approach in an elderly patient with severe cognitive impairment-a population routinely excluded from prospective trials. No radiation-related toxicities, including xerostomia or osteoradionecrosis, were documented during follow-up. These findings indicate that CT-guided [125]I seed brachytherapy with 3D-printed templates is a feasible, function-preserving and potentially curative treatment option for carefully selected elderly patients with advanced lip squamous cell carcinoma who are unable to tolerate conventional definitive therapy. These results further challenge the common view that interventional brachytherapy serves only as a palliative measure.},
}

@article {pmid42752707,
year = {2026},
author = {Santos, DH and da Silva, AMP},
title = {Amyloid-beta-targeting monoclonal antibodies in early Alzheimer's disease: a cochrane review summary and appraisal for the neurological community.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42752707},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal/therapeutic use ; *Amyloid beta-Peptides/immunology/metabolism ; Cognitive Dysfunction/drug therapy ; },
abstract = {BACKGROUND: Seven amyloid-beta-targeting monoclonal antibodies have been trialled in early Alzheimer's disease. They differ in epitope and in how much plaque they clear; only two have traditional approval. A 2026 Cochrane Review pooled all seven as one class. We ask what that average tells us about any one drug.

METHODS: We summarise the review in mild cognitive impairment or mild dementia due to Alzheimer's disease and report its estimates and certainty ratings unchanged. Our appraisal sits in a separate section and draws on the pivotal trials and regulatory assessments.

RESULTS: Seventeen trials (20,342 participants) were included. At 18 months the pooled standardised mean difference was -0.11 (95 % confidence interval -0.16 to -0.06) for cognition and -0.12 (-0.24 to 0.00) for dementia severity; three functional scales favoured treatment (0.09 to 0.23). Amyloid-related imaging abnormalities with oedema affected 119 versus 12 per 1,000 (risk ratio 10.02, 7.49 to 13.41). Four of the seven antibodies cleared no plaque or cleared it incompletely, so the pooled result cannot test whether clearance produces benefit. In the two approved agents dementia severity differed by 0.45 and 0.67 points, larger than the class average but below thresholds of clinical importance.

CONCLUSIONS: The class average is not an estimate for any single agent. These antibodies clear amyloid and produce small differences on trial scales at 18 months, against a tenfold rise in amyloid-related oedema. Counselling should rest on agent-specific figures and a biomarker-confirmed diagnosis, and should weigh APOE ε4 genotype and antithrombotic use before the first infusion.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal/therapeutic use
*Amyloid beta-Peptides/immunology/metabolism
Cognitive Dysfunction/drug therapy

@article {pmid42752992,
year = {2026},
author = {Li, X and Liu, X and Song, X and Zhou, Y and Yang, D and Wang, Y and Mao, S and Rang, X and Hong, X and Wang, X and Yue, H and Wang, D and Zhang, X},
title = {Bioinformatics-Driven Discovery of Aβ-Targeted Therapeutics and Diagnostic Biomarkers for Alzheimer's Disease.},
journal = {BioMed research international},
volume = {2026},
number = {1},
pages = {e8975137},
pmid = {42752992},
issn = {2314-6141},
support = {LH2020H052//Heilongjiang Provincial Natural Science Foundation/ ; },
mesh = {*Alzheimer Disease/diagnosis/metabolism/genetics/drug therapy ; Humans ; *Amyloid beta-Peptides/metabolism ; *Biomarkers/metabolism ; Molecular Docking Simulation ; *Computational Biology/methods ; Curcumin/pharmacology/chemistry ; Molecular Dynamics Simulation ; Resveratrol/pharmacology ; Apigenin/pharmacology/chemistry ; Gene Regulatory Networks ; Protein Binding ; },
abstract = {The deposition of amyloid-β (Aβ) plaque is widely recognized as one of the core pathological events of Alzheimer's disease (AD). This study focused on uncovering potential diagnostic biomarkers and small-molecule candidates potentially modulating Aβ-associated pathways in AD. Weighted gene coexpression network analysis (WGCNA) and machine learning identified the hub gene. Single-nucleus RNA sequencing (snRNA-seq) identified high-expression cell clusters. We identified potential Aβ-binding small-molecule candidates and calculated their binding affinities using molecular docking techniques. Based on molecular docking, we further evaluated the binding stability and conformational dynamics of the protein-ligand complex through molecular dynamics (MD) simulations. NFKBIA was identified as a hub diagnostic gene. Three small molecules, resveratrol, curcumin, and apigenin, demonstrated strong binding affinities for NFKBIA. These findings clarify the priority candidate gene and feasible strategic directions, which are expected to be translated into practical pathways for precision diagnosis and treatment of AD.},
}

*Alzheimer Disease/diagnosis/metabolism/genetics/drug therapy
Humans
*Amyloid beta-Peptides/metabolism
*Biomarkers/metabolism
Molecular Docking Simulation
*Computational Biology/methods
Curcumin/pharmacology/chemistry
Molecular Dynamics Simulation
Resveratrol/pharmacology
Apigenin/pharmacology/chemistry
Gene Regulatory Networks
Protein Binding

@article {pmid42746205,
year = {2026},
author = {Sharif, A and Mamo, JCL and Lam, V and Luna, G and Watts, GF and Nesbit, ML and Al-Salami, H and Mooranian, A and Takechi, R},
title = {Effects of HA1, a probucol analogue, and APOC3 siRNA on lipoprotein and amyloid-β metabolism and neurovascular dysfunction in type 2 diabetic mice.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1826957},
pmid = {42746205},
issn = {1663-9812},
abstract = {INTRODUCTION: Chronic vascular exposure to elevated levels of lipoprotein-amyloid-β (Aβ) contributes to blood-brain barrier (BBB) disruption and the pathogenesis of Alzheimer's disease (AD). Therapeutic agents such as probucol have been shown to reduce circulating lipoprotein-Aβ levels and mitigate neurovascular dysfunction and cognitive decline. Type 2 diabetes (T2D) impairs BBB integrity and is characterised by dyslipidaemia and metabolic disturbances that may influence the peripheral metabolism of lipoprotein-Aβ. However, the effects of diabetes on lipoprotein-Aβ homeostasis and neurovascular integrity remain poorly understood. This study investigated whether diabetes impairs lipoprotein and Aβ metabolism and whether treatment with HA1, a probucol analogue with improved bioavailability, or APOC3 siRNA can modify these metabolic changes and improve neurovascular and behavioural outcomes.

METHODS: Non-diabetic db/+ mice, untreated diabetic db/db mice, and diabetic db/db mice treated with HA1 or APOC3 siRNA were used to determine how diabetes and therapeutic modulation of lipoprotein metabolism affect circulating Aβ, neurovascular integrity, and behavioural outcomes. Total plasma Aβ and ApoB levels were measured by ELISA. Intestinal Aβ and ApoB, neurovascular integrity, neuroinflammation, and oxidative stress were assessed by immunofluorescence. Anxiety-like behaviour and short- and long-term memory were evaluated using the open field, novel object recognition, and passive avoidance tests.

RESULTS: Diabetic db/db mice exhibited increased intestinal Aβ and ApoB immunoreactivity and elevated total plasma Aβ42, Aβ oligomer and ApoB, accompanied by heightened BBB permeability and anxiety-like phenotype. HA1 reduced intestinal Aβ and lowered plasma Aβ42 and Aβ oligomer, prevented IgG extravasation, and improved anxiety. APOC3 siRNA lowered plasma ApoB and plasma Aβ42 and attenuated neuroinflammation, but did not reduce IgG extravasation.

CONCLUSION: Dysregulated lipoprotein and Aβ metabolism are associated with neurovascular dysfunction and anxiety-like behaviour in diabetes. HA1 shows therapeutic potential by modulating Aβ metabolism and improving neurovascular and behavioural outcomes.},
}

@article {pmid42746606,
year = {2026},
author = {Liu, AJ and Moghadam, AA and Alam, MS and Lutz, MW and Navarra, A and Luo, S and Wang, LA and Petrella, JR and Whitson, H and O'Brien, RJ and Johnson, KG and Parker, D and Beam, C and Sanfilippo, M and Al-Sahlani, H and Cobb, S and Liu, MY and Doraiswamy, PM},
title = {Clinical Practice Outcomes With Lecanemab for Alzheimer Disease.},
journal = {Neurology open access},
volume = {2},
number = {3},
pages = {e000121},
pmid = {42746606},
issn = {2998-7601},
support = {P30 AG072958/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND AND OBJECTIVES: Lecanemab, an antiamyloid monoclonal antibody, received US Food and Drug Administration approval in July 2023 to treat amyloid-positive early stages of Alzheimer disease (AD) and has since been adopted in many countries. The primary objective was to assess amyloid-related imaging abnormality (ARIA) incidence and serious adverse events. Secondary objectives included identifying ARIA predictors and evaluating its effect on 12-month cognitive change.

METHODS: We performed a retrospective, single-site observational study in patients treated with lecanemab at the Duke University (May 2023-June 2025). Eligible patients met National Institute on Aging-Alzheimer's Association criteria for mild cognitive impairment or mild AD with confirmed amyloid pathology. Treatment protocols and MRI interpretations were standardized.

RESULTS: Among 230 patients (68% MCI; mean age 73.6; 50.9% female; 67.4% allele producing the ε4 type of apolipoprotein E [APOE ε4] carriers), the mean follow-up was 396 days (SD 183). Forty-nine patients (21% [95% CI 16.3%-27.3%]) discontinued treatment. ARIA occurred in 56 patients (24.3% [95% CI 19.1%-30.5%]). ARIA with edema (ARIA-E) and ARIA with microhemorrhages (ARIA-MH) generally had a peak incidence rate at ~10 weeks, with a smaller ARIA-E peak at ~25 weeks; most moderate-to-severe events occurred between 12 and 24 weeks. Clinically significant adverse events occurred in 72 patients (31.3% [95% CI 25.5%-37.8%]), including 5 deaths (2 ARIA-related). Twelve-month cognitive changes did not significantly differ by ARIA status, although there was a significant decline of 0.107 [95% CI 0.04-0.17] units per month in the Montreal Cognitive Assessment score. ARIA-E risk was elevated in APOE ε4 carriers (OR 4.81 [95% CI 1.17-21.45] for 2 copies, p = 0.014) and in men (OR 2.40 [95% CI 0.88-7.25], p = 0.075). Baseline ptau-181/amyloid beta 42, APOE ε4, and Fazekas scores showed high specificity (>90%) but low sensitivity (<25%) for ARIA. Initiation of treatment earlier in the disease course was associated with fewer ARIA events, particularly among APOE ε4 noncarriers and those with lower baseline amyloid burden.

DISCUSSION: Despite the limitations of a single-site cohort, these findings inform real-world lecanemab safety and efficacy. Dual ARIA-E peaks at ~10 and ~25 weeks underscore the need for ongoing MRI monitoring. Although several markers showed modest negative predictive value, none reliably predicted ARIA. Improved markers to predict and monitor ARIA are needed to optimize cognitive outcomes.},
}